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ISRN Physiology
Volume 2013 (2013), Article ID 986320, 13 pages
http://dx.doi.org/10.1155/2013/986320
Review Article

Signalling in Neutrophils: A Retro Look

Department of Microbiology-Infectiology and Immunology, Faculty of Medicine, Laval University, Centre de Recherche du CHU de Québec, 2705 Boulevard Laurier, Room T 1-42, Québec, QC, Canada G1V 4G2

Received 18 August 2013; Accepted 17 September 2013

Academic Editors: D. Lominadze, F. Moccia, and M. J. Tuvim

Copyright © 2013 Paul H. Naccache. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This review presents a summary of signalling events related to the activation of human polymorphonuclear neutrophils by a variety of soluble and particulate agonists. It is not intended as a comprehensive review of this vast field or as a presentation of the multiple new aspects of neutrophil functions that are being documented at an ever faster rate. Its aim is rather to focus on multiple aspects of major signalling pathways that, in the view of this reviewer, are currently shadowed by present trends and to provide the core evidence for their implication and the limitations of our present knowledge. More specifically, this review starts with cell surface receptors and some of their functional and biological properties and then moves on to downstream transducers (G proteins) and effectors (the phosphoinositide, tyrosine kinases, and cyclic nucleotide pathways). Classical second messengers (calcium, protein kinase C, polyphosphoinositides, and cyclic nucleotides) are emphasized. It is hoped that this presentation will not only remind present-day investigators of the central role these pathways play in the regulation of the functional responsiveness of neutrophils, but that it will also highlight some of the areas deserving additional investigation.

1. Introduction

The role(s) of the polymorphonuclear neutrophil granulocyte (neutrophil) in the immune system is (are) rapidly evolving and expanding [1]. Long after having been recognized by Metchnikoff (cited in [2]) as a major player in the first line of defence of the organism, the multiple contributions of the neutrophil to the shaping of the immune response, both innate and acquired, are being recognized. Evidence for the phenotypic plasticity of the neutrophil as well as its functional diversity is rapidly accumulating [3]. This includes the realization that neutrophils can acquire the capacity to present antigens through the expression of MHC class II molecules [4, 5], to express functional elements of the T cell receptor [6], and to produce and secrete various cytokines and chemokines [7] that direct the differentiation and function of dendritic cells and T and B lymphocytes, that is, the effector arm of the immune system [1, 8].

In the following, I will review some of the early events related to signalling in neutrophils. In view of the width of the topic, the choices made will necessarily be arbitrary, and significant elements will be left out. The emphasis in this review will be on several aspects of signalling which have, to some extent, been relatively in the shadow recently with the recent emphasis on novel neutrophil functions [1]. It is intended to complement the information in the multiple excellent reviews on neutrophil signalling and functions (signalling: [911] and function: [8, 1220]) that have recently been published.

2. Historical Considerations Related to Signalling

Detailed studies of the signalling mechanisms associated with the regulation of neutrophil functions began in earnest in the 1970s. These studies were greatly aided by the ready availability of the cells (the most numerous blood borne leukocytes) and the identification by Schiffmann and his colleagues of bacterial-related molecular signals (the formylated peptides) that directed the movement of these cells [2123]. The latter breakthrough provided investigators with characterized agonists with which to stimulate the cells and the ability to identify specific biochemical events related to their functions. The functional identification of plasma membrane receptors and of specific signalling pathways rapidly followed. Although much remains to be clarified, three decades of evidence have since accumulated concerning the biochemical pathways associated with various neutrophil responses. This has, inter alia, illustrated the complexity of the regulatory mechanisms and the limits of our present understanding and, in so doing, indicates the directions of future studies.

3. Signalling in Neutrophils

3.1. Receptors

Classical pharmacological evidence for the presence of receptors on the neutrophil plasma membrane rapidly followed the identification of chemotactic factors (formylated peptides, C5a, leukotriene B4, and interleukin 8 ). The subsequent development of molecular biology tools led to the molecular characterization of these entities. Receptors for chemotactic factors, opsonins, cytokines, Toll-like receptors, neuropeptides, and growth factors, among others, have since been identified on the plasma membrane of neutrophils.

These receptors belong to multiple categories. They include G protein- (most chemotactic factors), tyrosine kinase- (directly or indirectly) as well as adenylyl and guanylyl cyclase (the latter will not be dealt with in this review) coupled receptors.

While most, if not all, of these receptors are transmembrane proteins, signal transduction mediated by direct perturbation of the lipid bilayers (as opposed to interaction with surface protein receptors), possibly at the level of lipid rafts, cannot be excluded in some cases, for example, in response to monosodium urate crystals (the etiological agent of gout) [24].

3.1.1. Multiple Ligands for Same Receptors

While receptors recognize specific ligands, they may also recognize multiple ligands as exemplified by the chemokine receptors for CXCL8 (IL-8). For example, the CXCL8 receptor, CXCR1, binds and responds to CXCL8 as well as to CXCL7 (NAP-2) and CXCL1 (Gro- ). The formyl peptide receptor (FPR) binds not only formylated peptides but recognizes and responds also to the antimicrobial granule proteins cathepsin G [25] and to cryptic peptides of HIV-1 envelope proteins [2628], while serum amyloid A [29] (see, however, [30, 31] for an opposing view) and the antimicrobial peptide LL-37 [32] interact with formyl peptide receptor-like 1 (FPRL1). Similarly, Fc Rs may recognize acute phase proteins such as C-reactive proteins [33, 34] in addition to the Fc tail of immunoglobulins, and the danger signal HMGB1 may interact with the LPS receptor TLR4 [35].

3.1.2. Multiple G Proteins for Same Receptor

Additional levels of complexity are provided by the observations that receptors for the same ligands (e.g., CXCR1 and CXCR2) may couple to distinct G proteins [36] and that specific G protein subunits may mediate different functions [37].

3.1.3. Multiple Functions for Same Receptor

Signalling through a single receptor does not necessarily lead to the activation of the same intracellular pathways depending on the ligand recognized. For example, IL-8 and Gro- may not be perceived equivalently by neutrophils. In human neutrophils, only Gro- , but not IL-8, induces an influx of calcium. These results were confirmed in HEK 293 cells expressing CXCR1 or CXCR2 indicating that the consequences of the binding of IL-8 and Gro- to CXCR2 are distinct [38].

3.1.4. Receptor Multimerization

The receptors expressed on neutrophils may function, at least in part, in a high-order complex involving homo- or heterodimerization that leads to distinct signalling outcomes [39]. Chemokine receptor trafficking to the cell membrane is likely to occur as oligomers [40]. The dimerization status of CXCR1 and CXCR2 is modulated both by receptor expression and by their ligands. For example, CXCL8 decreases heterodimerization of CXCR1 and CXCR2 while stabilizing homodimers and stimulating internalisation of both receptors [41]. Oligomerization may involve more than one receptor family, and interactions between the complement fragment receptor C5aR and CCR5 leading to cointernalization of the receptors have been described [42]. The mechanisms by which the GPI-linked Fc R CD16b transmits its signals to the interior of the cells are still unresolved, but they may involve the interactions of CD16b with the integrin CD11b [4346].

3.1.5. Receptor Internalization

Internalization of many neutrophil receptors has been observed. This includes receptors for chemoattractants such as fMLF, C5a and IL-8 (e.g., [47]) as well as opsonins (CD32a, CD16b) [48, 49]. Different regions of the carboxy-terminus of the receptors have been identified that play a role in these events mediated in part by phosphorylation. For example, IL-8-dependent internalization of CXCR1 is dependent on a region of the carboxy terminal of the receptor that includes multiple phosphorylation sites. IL-8-induced CXCR2 internalization on the other hand relies on a different, membrane-proximal region of the carboxy-terminus [50]. These results are consistent with the observations that the internalization of CXCR1/2 that follows stimulation by IL-8 is decreased by truncation of the last (C-terminal) amino acids of the receptors [5153]. Kinases such as the GRK family (and GRK2 in particular) and PKC have been reported to be involved in the regulation of the internalization of the receptors. The phosphorylation sites are likely to be located in the C-terminal region of the receptors. Arrestins and dynamin also play a role in the internalization of CXCR1/2 which appears to be independent of the interaction with heterotrimeric G proteins as FPR internalization is not affected by pertussis toxin [54]. Engagement of the opsonin receptor CD32a similarly leads to its internalization and subsequent proteosomal degradation [49].

Internalization of the chemoattractant receptors is transient and followed by a recycling to the plasma membrane while that of CD32a results in its proteasome-dependent degradation [48, 49]. The mechanisms regulating receptor recycling differ from those involved in their internalization; for example, recycling, as opposed to internalization, of CXCL8 receptors is phosphorylation independent [50, 53]. GPCR phosphorylation is likely to be mediated by G protein-coupled receptor kinase 2 [55]. The mechanisms regulating receptor recycling vary from receptor to receptor; C5aR recycling is inhibited potently by monensin, while that of FPR is not [56]. This indicates that cells may differentially regulate receptor recycling.

3.2. Coupling of Neutrophil Receptors

The major receptors on neutrophils (chemoattractant and opsonin receptors) are coupled to two principal intermediaries, heterotrimeric G proteins and tyrosine kinases. These systems serve to relay the information conveyed by the occupancy of the receptors to the cells’ interior, provide an initial amplification stage, and are responsible for the appropriate activation of the required downstream effector systems.

3.2.1. Coupling to G Proteins

The receptors for most chemoattractants including those for formylated peptides, chemokines such as CXCL1,2 or 8 (CXCR1,2), the complement fragment C5a, and the lipid mediators platelet-activating factor (PAF) and leukotriene B4 (LTB4) are all coupled to heterotrimeric G proteins. Neutrophils express a variety of heterotrimeric G proteins and in particular those of the Gs, Gi, and Gq families. The best characterized functions of the chemotactic factor receptors are linked to the activation of G proteins of the Gi family and in particular Gi 2 and Gi 3. Experimentally, this is manifested by the sensitivity to inhibition by pertussis toxin, the toxin from Bordetella pertussis [5759]. The inhibition by pertussis toxin of chemotaxis, degranulation, and the stimulation of the oxidative burst as well as of several signalling pathways (calcium mobilization, actin polymerization, and stimulation of tyrosine phosphorylation) provided the first indices of the involvement of Gi or Gi-like proteins in signal transduction in neutrophils [57, 60, 61]. The results of Damaj et al. [62] describing the inhibitory effects of peptides derived from Gi 2 (but not Gi 1 or Gi 3) on the coimmunoprecipitation of CXCR1 and CXCR2 and Gia2 as well as on the mobilization of calcium induced by CXCL8 are consistent with this interpretation and additionally indicate that CXCR1 and CXCR2 specifically associate with Gi 2. Pertussis toxin-insensitive G proteins of the Gq family (Gia16) are also expressed in neutrophils and may mediate some neutrophil responses [63]. Occupation of the chemoattractant receptors and activation of heterotrimeric G proteins follow the well described and by now canonical activation sequence of exchange of GDP for GTP on the subunit of the G proteins, dissociation of the and - subunits, and interaction with downstream effectors.

The and subunits of the heterotrimeric G proteins involved in the responses of human neutrophils are likely to be linked to specific signalling pathways (e.g., and PI 3-kinases [64, 65]). This remains to be elucidated in detail in the context of individual agonists.

3.2.2. Coupling to Tyrosine Kinases

The neutrophil opsonin receptors CD32a and CD16b do not interact, at least not directly, with heterotrimeric G proteins. Instead, their dimerization induced upon their engagement leads to the recruitment and activation of tyrosine kinases of three major families, Src, Syk, and Tec [66]. Enhanced levels of tyrosine phosphorylation upon engagement of CD32a or CD16b have been observed. Pharmacological as well as genetic information indicates that Src kinases are mobilized upon the engagement of CD32a and of CD16b upstream of Syk. The latter plays a crucial role in the regulation of phagocytosis [6769]. The Src kinases implicated (Fgr, Hck, and Lyn), in particular in response to different modes of stimulation of CD32a and CD16b, remain to be unambiguously identified. Though a significant level of redundancy between Src family kinases is illustrated by the requirement for double or triple knockout of these kinases for the clear demonstration of functional effects [70, 71], it is also apparent that they control different and specific aspects of the internalization/recycling cycle in neutrophils [71, 72]. The activation of Tec family kinases in response to the engagement of CD32a and CD16 [73] as well as to stimulation with monosodium urate crystals has also been reported. The latter stimuli appear to rely specifically on Tec to mediate their phlogistic activity [74, 75].

Tyrosine kinases of the Src family are also activated upon occupation of chemoattractant receptors (e.g., [76]; see reviews [77, 78]). Direct evidence for the activation of Src family kinases (increased kinase activity, enhanced tyrosine phosphorylation) by chemotactic factors as well as inhibition of signalling and functional responses to these same agonists by potent Src family kinase inhibitors has been repeatedly described. As is the case for opsonin receptors, the Src family of tyrosine kinases play redundant roles in the responses to chemoattractants also [70, 71]. Silencing of single members of the Src family members has little if any effect on the functional responsiveness of neutrophils to chemotactic factors. On the other hand, while silencing of both Hck and Fgr failed to inhibit the mobilization of calcium, the phosphorylation of Akt and of MAPK ERK1 and ERK2 and neutrophil migration in response to fMLF, deficient signalling to the respiratory burst, the polymerization of actin, and the phosphorylation of vav1 and of the p21-activated kinases were observed [70].

The detailed molecular mechanisms by which G protein-coupled receptors activate Srk kinase remain to be satisfactorily characterized. In view of the inhibitory effects of pertussis toxin on the activation of Src kinases by chemotactic factors, it is highly likely that these kinases are responding either directly or indirectly to activated (GTP-bound, dissociated) heterotrimeric G proteins. G proteins and Src family kinases, as well as some chemoattractant receptors (e.g., BLT1 but not FPR [79]), have been observed in lipid rafts which may provide the proximity required for the activation of the latter.

Tyrosine kinases other than Src and Syk family kinases are also involved in the responses of human neutrophils to GPRs. Prominent among these are the Tec family kinases [80, 81]. On the other hand, Syk which plays a crucial role in the control of phagocytosis (see above) is not stimulated upon the activation of chemoattractant receptors. A complex interrelationship exists between the activation of Tec kinases and PI 3-kinases. The stimulation of the former is inhibited by the pan-PI3kinase inhibitor wortmannin [80], while the accumulation of PtdIns(345)P3 in response to fMLF is itself decreased by the Tec kinase inhibitor LFM-A13 [81]. It should be pointed out however that direct effects of LFM-A13 on the binding of fMLF to FPR1 have not been rigorously ruled out and may explain the inhibition of the mobilization of calcium by the former in response to fMLF [78] which is not observed with a variety of potent tyrosine kinase inhibitors (e.g., PP1 and PP2 (Naccache et al., unpublished observations)). The activation of Syk by monosodium urate crystals, the etiological agent of gout, has also been reported [74, 82, 83]. It should be pointed that the activation of Tec family kinases and of Syk occurs downstream of that of Src family kinases.

Evidence for the involvement of the tyrosine kinase FAK, at least in murine systems, has been reported [84]. However, no direct evidence for the expression by FAK in human neutrophils is available, and FAK is abundantly expressed in platelets which are likely to contaminate to a significant extent most, if not all, neutrophil preparations routinely used.

Recent results indicate that the cytosolic tyrosine kinase c-Abl is critically involved downstream of Src kinases in response to the occupation and activation of -integrins. The ubiquitous kinase c-Abl is implicated in regulating membrane ruffling, cell spreading, cytoskeletal dynamics, and extension of filopodia in various cell types and fibroblasts in particular. Pharmacological inhibition or genetic knockdown of c-Abl inhibited neutrophil recruitment in a thioglycollate-induced peritonitis as well as the in vitro chemotactic movement of neutrophils [85]. The activation of c-Abl appears specific to the engagement of -integrins and is not observed in response to stimulation by fMLF in cells in suspension. It occurs downstream of Src kinases, and accordingly, inhibition of Src kinases decreases c-Abl activation [85], and tripartite complexes of Fgr or Hck and c-Abl have been detected in -integrin immunoprecipitates [86]. The link between c-Abl and the cytoskeleton appears to involve the adaptor protein Vav1 whose tyrosine phosphorylation upon -integrin activation is profoundly decreased upon the inhibition of c-Abl [85]. It remains to be understood why -integrins but not fMLF (which both activate Src kinases) stimulate the c-Abl signalling pathway.

As described below, the activation of tyrosine kinases, in response to opsonin or chemoattractant receptors, plays major signalling roles in the regulation of the functional responsiveness of human neutrophils.

3.3. Downstream Effector Pathways

A number of well-characterized signalling pathways lay downstream from heterotrimeric G proteins and/or tyrosine kinases. These include the phospholipase C and the phosphatidylinositol 3-kinase pathways; the activation of either further leads to the stimulation of a variety of signalling intermediates.

3.3.1. Calcium

Transient increases in the cytosolic concentrations of free calcium are an early response of human neutrophils to most of their pathophysiological agonists [87]. Increases in free cytoplasmic calcium (up to close to 1  M) are detected within seconds of stimulation by a variety of neutrophil agonists including chemotactic factors [8890], opsonin receptor engagement, and phlogistic microcrystals. They last a few minutes before the cytosolic levels of calcium are restored to their prestimulation levels (about 0.1  M). Longer lasting calcium oscillations driven by increased calcium influx have been detected upon stimulation of human neutrophils by immune complexes [91].

The stimulated increases in cytosolic free calcium play a central role in the initiation and modulation of the functional responsiveness of neutrophils having been linked to the regulation of most, if not all, neutrophil functions including chemotaxis, phagocytosis, degranulation, and the stimulation of the oxidative burst.

The mobilization of calcium in nonexcitable cells derives from a combination of release from intracellular stores and enhanced influx from the extracellular milieu. This, by now classical, paradigm was derived [88] before the role of Ins(3,4,5)P3 in the mobilization of intracellular calcium was discovered by Berridge and collaborators (reviewed in [36]).

The role of phospholipase C-derived inositol(1,4,5)-trisphosphate (Ins(1,4,5)P3) in the release of calcium from intracellular stores is well established [36], though it should be noted that the nature of the endoplasmic reticulum-associated intracellular stores of calcium (originally termed calciosomes [92]) remains to be directly characterized in neutrophils.

The nature of the link, if any, between the emptying of the calcium stores into the cytoplasm and the regulation and nature of the plasma membrane calcium channels involved in the influx of calcium is another element that requires further investigation (see below).

(1) Phospholipase C. The increases in cytosolic free calcium are mediated by the activation of one or more phospholipase C (PLC), and the attendant hydrolysis of phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P2) leading to the generation of inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) and diacylglycerol (DAG). Ins(1,4,5)P3 plays a major role in the release of calcium from intracellular stores through its binding to specific receptors located on the intracellular storage organelles. Neutrophils express both PLC and PLC isoforms of PLCs, and these are differentially activated depending on the type of receptors engaged (GPCR- versus tyrosine-kinase coupled, resp.).

(a) PLC . The evidence for the involvement of the G protein-coupled PLC in the mediation of the responses to the occupation of chemoattractant receptors derives from the evidence of the stimulated hydrolysis of PtdIns(4,5)P2 [93] and the inhibitory effects of pertussis toxin on the responses of neutrophils to chemotactic factors [59, 60]. Little direct evidence for the stimulation of the activity of PLC is available, however. Nevertheless, the activation of a non-identified PLC by fMLF in rat neutrophils in the presence of GTP S has been reported [94]. Most if not all chemotactic factors for neutrophils depend on PLC 2 to mediate the responses to receptors for chemotactic factors [95]. It is possible that some of these receptors may be coupled, in addition to Gi, to G proteins of the Gq family. The lack of sensitivity of the responses to PAF to pertussis toxin [96] and the ability of G 16 (a member of the pertussis toxin-insensitive Gq family) to interact with the C5a receptor [97] support, inter alia, this possibility.

Silencing of PLC 2 enhanced, unexpectedly, rather than inhibited the chemotaxis of neutrophils from knockout mice to fMLF and CXCL8 [98]. The mechanistic explanation for this (puzzling) observation is still lacking.

(b) PLC 2. The occupation of tyrosine kinase-coupled receptors such as opsonin receptors (CD32a, CD16b, and CD11b) calls into action PLCs of the PLC family and PLC 2 in particular as evidenced by its enhanced tyrosine phosphorylation upon receptor engagement [99101].

The nature of the tyrosine kinase involved in the activation of PLC 2 upon the engagement of opsonin receptors in neutrophils remains to be unambiguously identified. The known activation of Src kinases by the engagement of these receptors, coupled to the inhibitory effects of highly specific Src kinase inhibitors on the responses, including the mobilization of calcium, makes it highly likely that one or more of the Src kinases may be involved. Lyn is likely to play a role in the phosphorylation of the ITAM of CD32a [76], possibly subsequently to the translocation of the latter to detergent-resistant domains where the kinase resides [102, 103]. Furthermore, direct evidence of the activation of Lyn upon the cross-linking of CD32a [104] and by particulate agonists (monosodium urate crystals) has also been reported [76]. The presently available data cannot define or exclude, however, contributions of the other members of the Src family of kinases to the responses to the engagement of opsonin receptors in human neutrophils.

(2) SOCE and Its Limitations. Calcium mobilization in human neutrophils in response to stimulation by most agonists, and in particular fMLF, conforms to the often described model in which Ins(3,4,5)P3-dependent release of calcium from intracellular stores (and their concomitant emptying) leads to the opening of plasma membrane calcium channels and an influx of calcium from the extracellular milieu. This is usually referred to as the “store-operated calcium entry” (or SOCE) model [105]. The link between the emptying of the intracellular stores (and indeed their specific identity) and the opening of the plasma membrane calcium channels remains to be characterized in details although the contribution of endoplasmic reticulum-associated Stim-1 and plasma membrane-associated Orai proteins (forming the calcium channels termed ICRAC) appears highly likely [106109].

Evidence for means of mobilization of calcium (and in particular calcium influx) in human neutrophils other than through SOCE has also been obtained. For example, whereas engagement of CD32a leads to a rapid and robust mobilization of calcium in human neutrophils, this is not accompanied by a stimulation of calcium influx [110]. On a similar note, while both CXCL-8 and CXCL-1 bind to the same receptors on human neutrophils (CSCR8) and induce a quantitatively similar mobilization of calcium (though that induced by CXCL-1 is longer lasting), only the latter induces a detectable influx of calcium from the extracellular medium [38]. Furthermore, pharmacological evidence for ICRAC-independent means of mobilizing calcium in human neutrophils has also been reported [111114]. This includes the observations that the piperazine compound ML-9 inhibits thapsigargin-induced but not the receptor-operated calcium influx and that the SOCE inhibitor Gd3+ only partially inhibits the influx of calcium induced by fMLF. Additionally, fMLF stimulates the influx of Sr2+ (an index of receptor-operated calcium entry or ROCE). These results indicate that the link between the emptying of the calcium stores and the opening of the calcium channels can be uncoupled and is dependent on specific, as yet unidentified, intracellular signals that deserve further examination. The potential contribution of arachidonate-regulated calcium channels (termed ARC) [115] as well as of TRP channels (known to be expressed in human neutrophils [116, 117]) to the SOCE-independent calcium influx deserves to be investigated in additional details and in particular in the context of stimulation by various chemoattractants which may depend differentially on distinct calcium channels [118].

(3) Protein Kinase C. In addition to generating the intermediate for the release of intracellular calcium, Ins(3,4,5)P3, the activation of PLC leads to the formation of the bioactive lipid mediator diacylglycerol or DAG. One of the major signalling pathways dependent on the generation of DAG is that reliant on the activity of a family of serine/threonine kinases known as protein kinase C or PKC.

The PKC family comprises at least ten members subdivided among three subgroups depending on their cofactor requirements [119, 120]. The conventional PKCs (cPKC), of which at least two members are expressed in neutrophils (PKC- and PKC- ), require binding of phosphatidylserine, DAG, and calcium for activation. Phorbol are esters can substitute for DAG [121]. Novel PKCs (nPKC), of which PKC is present in neutrophils, are calcium insensitive, but, as cPKC, DAG and phorbol ester sensitive. Finally, atypical PKCs (aPKCs) do not respond to calcium or to DAG. Whether they are expressed in human neutrophils remains to be rigorously established, although their presence in rat neutrophils has been reported [122].

The ability of phorbol esters to activate neutrophils has been reported as early as the mid-1970s [123125]. In human neutrophils, phorbol esters, inter alia, potently activate the oxidative burst [126] and induce a limited but extensive degranulation of specific granules [125]. The stimulation of the NADPH oxidase by PKCs is closely related to their ability to phosphorylate p , one of the molecular components of this complex [127]. The selective secretion of specific granules induced by phorbol esters is itself likely the result of the lack of increases in the levels of cytoplasmic free calcium by this agonist [128] as the simultaneous addition of calcium ionophores results in complete neutrophil degranulation.

The use of phorbol esters has revealed intimate and complex relationships between PKCs and neutrophil activation. Preincubation with phorbol esters has complex and opposite effects on the subsequent functional responsiveness of neutrophils to chemotactic factors. Short incubation times and low concentrations (nM) of phorbol esters enhance the mobilization of calcium induced by fMLF [129] possibly, though this has not been tested, by recruiting PLC in addition to the G protein-coupled PLC . On the other hand, high concentrations ( M) of phorbol esters inhibit potently the same responses [130] at the same time as they inhibit the stimulation of the GTPase activity of the -subunit of Gi induced by fMLF [131]. It is tempting to extrapolate from these results and speculate, in vivo, the early phases of neutrophil recruitment which involve modest activation of chemotactic factor receptors and integrins (and a concomitant relatively weak stimulation of PKC) and that this may synergize to stimulate the functional responsiveness of neutrophils. On the other hand, upon prolonged stimulation of these two receptor types such as would be expected at the site of infection (and an accentuated activation of downstream effector pathways, including PKC), inhibition of chemotactic factor receptor-mediated signal transduction would contribute to neutrophil arrest and the performance of their phagocytosis-related functions.

Complex and incompletely understood relationships between the activation of PKCs and that of tyrosine kinases exist in neutrophils. Some of the earliest evidence for these interrelationships came from the observation that phorbol esters altered the pattern of tyrosine phosphorylation induced by fMLF [129]. The ability of phorbol esters to inhibit the activation of Lyn and the tyrosine phosphorylation of the p85 subunit of PI 3-kinase and its subsequent activation [132] provides evidence for a role of PKC upstream of the lipid kinases. These observations are consistent with the more recent findings of Popa-Nita et al. [83] that the tyrosine kinase Syk is a substrate of PKC and that the PKC-mediated serine phosphorylation of Syk is necessary for its interaction with the p85 subunit of PI 3-kinase and its activation. Interactions between PKCs and Src family tyrosine kinases have been reported in various other cellular systems [133135].

The data described above indicates that PKC modulates the activity of tyrosine kinases. In cellular systems other than neutrophils, data have also been obtained indicating that PKCs can themselves be tyrosine phosphorylated and that these events modulate their activity [136, 137].

Some of the interrelationships just described may result from the direct association of PKCs and tyrosine kinases such as observed in platelets [138].

(4) Phosphatidylinositol 3-Kinases. A substantial body of evidence has implicated phosphatidylinositol 3-kinases (PI3Ks) in the regulation of the functional responsiveness of human neutrophils. This includes both direct measurements of the functional activation of these lipid kinases, measurements (direct and indirect) of the levels of the products generated upon their activation, the results of genetic manipulation in murine models, and the use of pharmacological agents.

Of the multiple PI3Ks, it is the class I PI3Ks (both class IA and IB) which are of direct relevance to the early events of the activation of human neutrophils [139, 140]. This subset of PI3Ks comprises tyrosine phosphorylation (class IA) and G protein (class IB) dependent members, namely, PI3K , PI3K , and PI3K for the former and PI3K for the latter.

Direct evidence for the activation of PI3Ks is available. The initial indication of the implication of PI3Ks in the responses of human neutrophils came from the measurement of the stimulated accumulation of the product of PI3Ks, namely, PtdIns(3,4,5)P3 [141, 142]. Accumulation of PtdIns(3,4,5)P3 in response to the engagement of CD32a has also been reported [143]. Rapid activation (within seconds) of PI3K by GPCRs (fMLF) has been documented [144].

The stimulation of the activity of PI3Ks may come directly upon the activation of G proteins through the interaction of the dissociated subunit with the regulatory p101 subunit as in the case of PI3K [145] (with an additional contribution for optimal activation of GTP-Ras [146]) or secondarily to the activation of tyrosine kinases and Src family kinases in particular, upon the interaction of the SH2 domains of the p85 regulatory subunit of class IA PI3Ks with phosphotyrosines on adaptor proteins. GTP-Ras plays a role, here too, in the optimal activation of the p110 catalytic subunit. In the case of 2 integrins and Fc Rs, these adaptor proteins include DAP12 and the Fc chain [147].

Pharmacological as well as genetic approaches have provided evidence for class I PI3Ks in the regulation of neutrophil adhesion, chemotaxis and recruitment, and phagocytosis and bactericidal activity (mostly through the regulation of the assembly and activation of the NADPH complex) [148150]. Introduction of dominant negative mutants of p85 and of p110 in the myeloid cell line PLB-985 differentiated to express a neutrophil-like phenotype indicates that only class IA PI3Ks are involved in the regulation of the chemotactic and oxidative responses to fMLF, though PI3K is mostly responsible for the initial peak of accumulation of PtdIns(3,4,5)P3 [151].

(5) Cyclic Nucleotides. Most neutrophil functions are inhibited by pharmacological manipulations that increase the levels of intracellular increase cAMP (e.g., [152159]). Stimulation of neutrophils by various agonists leads to rapid and transient increases in cAMP [160162]. The increases in cAMP may be due to an inhibition of phosphodiesterases [37] rather than to a stimulation of adenylyl cyclase. Evidence that the cAMP responses to the chemoattractant fMLF are secondary to the accumulation of adenosine has been obtained [163, 164]. The implication of the heterotrimeric G protein Gs, which is known to be present and active in neutrophils [165, 166], in the mediation of the increases of cAMP in neutrophils remains to be investigated. The role of cAMP in dampening neutrophil responses, while generally admitted, is however far from being completely understood as is the cAMP-mediated regulation of gene transcription in neutrophils [167, 168].

Very little is known about the potential involvement of cyclic GMP in the responses of human neutrophils though it is generally assumed to play a role opposite to that of cAMP in a manner consistent with the Yin-Yang hypothesis [169]. Accordingly, cyclic GMP enhances while cAMP inhibits neutrophil chemotaxis [165]. The intriguing results of Coffey et al. [170] linking the priming effects of GM-CSF to a stimulation of guanylyl cyclase coupled to an inhibition of adenylyl cyclase remain to be revisited.

(6) Other Signalling Pathways. The implication of various other signalling pathways in the regulation of the functional responsiveness of human neutrophils has been documented. These include, inter alia, the MAPK pathway, protein tyrosine phosphatases, serine/threonine phosphatases, small molecular weight G proteins of the Rho, and Rac and Arf families (and their relationship to the activation of the phospholipase D pathway and to the organization of the motor of the neutrophil, the actin cytoskeleton). Information about these events can be found in the reviews listed at the beginning of this paper.

4. Closing Remarks

As briefly summarized above as well as in the cited literature, a vast amount of detailed information about “signalling in neutrophils” is now available. The major pathways stimulated upon the engagement of a variety of surface receptors, with which the neutrophil is richly endowed, have been identified. Several central challenges remain however. As mentioned in the introduction, our understanding of the role(s) and function(s) of the neutrophil in innate as well as acquired immunity has vastly expanded in recent years. The manner in which this cell recognizes the clues that direct and control its functional and phenotypic plasticity, that is, the specific pathways which are called upon and their order and intensity, remain to be elucidated on an individual basis.

It is also clear that neutrophils will rarely, if ever, be exposed to a single class of agonists in vitro and that the extracellular environment and the extracellular matrix play major roles in directing and redirecting neutrophil responses (including the control of transcriptional programmes [171]). This is intimately related to the development of neutrophil subtypes and activated phenotypes that are likely to be encountered at inflammatory and tumor sites [172, 173]. This is another area that will require a sustained attention in coming years. A corollary of this is that the influence of other cell types, including endothelial cells, monocyte/macrophages, and platelets (e.g., [174176]), as well as that of the variety of extracellular vesicles that have been identified by now (microvesicles, exosomes ) [177] on the functional responsiveness of neutrophil can no longer be ignored in the perspective of deriving a more complete picture of this cell’s pathophysiological role(s).

References

  1. A. Mocsai, “Diverse novel functions of neutrophils in immunity, inflammation, and beyond,” The Journal of Experimental Medicine, vol. 210, pp. 1283–1299, 2013. View at Publisher · View at Google Scholar
  2. F. C. Schmalstieg Jr. and A. S. Goldman, “Birth of the science of immunology,” Journal of Medical Biography, vol. 18, no. 2, pp. 88–98, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. M. Beyrau, J. V. Bodkin, and S. Nourshargh, “Neutrophil heterogeneity in health and disease: a revitalized avenue in inflammation and immunity,” Open Biology, vol. 2, Article ID 120134, 2012. View at Publisher · View at Google Scholar
  4. N. A. Fanger, C. Liu, P. M. Guyre et al., “Activation of human T cells by major histocompatability complex class II expressing neutrophils: proliferation in the presence of superantigen, but not tetanus toxoid,” Blood, vol. 89, no. 11, pp. 4128–4135, 1997. View at Scopus
  5. E. J. Gosselin, K. Wardwell, W. F. C. Rigby, and P. M. Guyre, “Induction of MHC class II on human polymorphonuclear neutrophils by granulocyte/macrophage colony-stimulating factor, IFN-γ, and IL-3,” Journal of Immunology, vol. 151, no. 3, pp. 1482–1490, 1993. View at Scopus
  6. K. Puellmann, W. E. Kaminski, M. Vogel et al., “A variable immunoreceptor in a subpopulation of human neutrophils,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 39, pp. 14441–14446, 2006. View at Publisher · View at Google Scholar · View at Scopus
  7. P. Scapini, J. A. Lapinet-Vera, S. Gasperini, F. Calzetti, F. Bazzoni, and M. A. Cassatella, “The neutrophil as a cellular source of chemokines,” Immunological Reviews, vol. 177, pp. 195–203, 2000. View at Scopus
  8. A. Mantovani, M. A. Cassatella, C. Costantini, and S. Jaillon, “Neutrophils in the activation and regulation of innate and adaptive immunity,” Nature Reviews Immunology, vol. 11, no. 8, pp. 519–531, 2011. View at Publisher · View at Google Scholar · View at Scopus
  9. G. Cicchetti, P. G. Allen, and M. Glogauer, “Chemotactic signaling pathways in neutrophils: from receptor to actin assembly,” Critical Reviews in Oral Biology and Medicine, vol. 13, no. 3, pp. 220–228, 2002. View at Scopus
  10. V. Niggli, “Signaling to migration in neutrophils: importance of localized pathways,” International Journal of Biochemistry and Cell Biology, vol. 35, no. 12, pp. 1619–1638, 2003. View at Publisher · View at Google Scholar · View at Scopus
  11. Y. Wang, C.-L. Chen, and M. Iijima, “Signaling mechanisms for chemotaxis,” Development Growth and Differentiation, vol. 53, no. 4, pp. 495–502, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. D. C. Dale, L. Boxer, and W. Conrad Liles, “The phagocytes: neutrophils and monocytes,” Blood, vol. 112, no. 4, pp. 935–945, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. B. Amulic, C. Cazalet, G. L. Hayes, K. D. Metzler, and A. Zychlinsky, “Neutrophil function: from mechanisms to disease,” Annual Review of Immunology, vol. 30, pp. 459–489, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. C. Nathan, “Neutrophils and immunity: challenges and opportunities,” Nature Reviews Immunology, vol. 6, no. 3, pp. 173–182, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. S. J. Galli, N. Borregaard, and T. A. Wynn, “Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils,” Nature Immunology, vol. 12, no. 11, pp. 1035–1044, 2011. View at Publisher · View at Google Scholar · View at Scopus
  16. S. Jaillon, M. R. Galdiero, D. Del Prete, M. A. Cassatella, C. Garlanda, and A. Mantovani, “Neutrophils in innate and adaptive immunity,” Seminars in Immunopathology, vol. 35, no. 4, pp. 377–394, 2013. View at Publisher · View at Google Scholar
  17. S. Caielli, J. Banchereau, and V. Pascual, “Neutrophils come of age in chronic inflammation,” Current Opinion in Immunology, vol. 24, pp. 671–677, 2012. View at Publisher · View at Google Scholar
  18. A. Cerutti, I. Puga, and G. Magri, “The B cell helper side of neutrophils,” Journal of Leukocyte Biology, vol. 94, no. 4, pp. 677–682, 2013. View at Publisher · View at Google Scholar
  19. C. I. Timar, A. M. Lorincz, and E. Ligeti, “Changing world of neutrophils,” Pflügers Archiv, 2013. View at Publisher · View at Google Scholar
  20. H. L. Wright, R. J. Moots, R. C. Bucknall, and S. W. Edwards, “Neutrophil function in inflammation and inflammatory diseases,” Rheumatology, vol. 49, no. 9, pp. 1618–1631, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. E. Schiffmann, B. A. Corcoran, and S. M. Wahl, “N formylmethionyl peptides as chemoattractants for leucocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 72, no. 3, pp. 1059–1062, 1975. View at Scopus
  22. E. Schiffmann, H. V. Showell, B. A. Corcoran, P. A. Ward, E. Smith, and E. L. Becker, “The isolation and partial characterization of neutrophil chemotactic factors from Escherichia coli,” Journal of Immunology, vol. 114, no. 6, pp. 1831–1837, 1975. View at Scopus
  23. H. J. Showell, R. J. Freer, S. H. Zigmond et al., “The structure activity relations of synthetic peptides as chemotactic factors and inducers of lysosomal enzyme secretion for neutrophils,” Journal of Experimental Medicine, vol. 143, no. 5, pp. 1154–1169, 1976.
  24. Y. Shi, A. D. Mucsi, and G. Ng, “Monosodium urate crystals in inflammation and immunity,” Immunological Reviews, vol. 233, no. 1, pp. 203–217, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. R. Sun, P. Iribarren, N. Zhang et al., “Identification of neutrophil granule protein cathepsin G as a novel chemotactic agonist for the G protein-coupled formyl peptide receptor,” Journal of Immunology, vol. 173, no. 1, pp. 428–436, 2004. View at Scopus
  26. S. B. Su, W.-H. Gong, J.-L. Gao et al., “T20/DP178, an ectodomain peptide of human immunodeficiency virus type 1 gp41, is an activator of human phagocyte N-formyl peptide receptor,” Blood, vol. 93, no. 11, pp. 3885–3892, 1999. View at Scopus
  27. S. B. Su, J.-L. Gao, W.-H. Gong et al., “T21/DP107, a synthetic leucine zipper-like domain of the HIV-1 envelope gp41, attracts and activates human phagocytes by using G-protein-coupled formyl peptide receptors,” Journal of Immunology, vol. 162, no. 10, pp. 5924–5930, 1999. View at Scopus
  28. A. de Paulis, G. Florio, N. Prevete et al., “HIV-1 envelope gp41 peptides promote migration of human FcεRI+ cells and inhibit IL-13 synthesis through interaction with formyl peptide receptors,” Journal of Immunology, vol. 169, no. 8, pp. 4559–4567, 2002. View at Scopus
  29. S. B. Su, W. Gong, J.-L. Gao et al., “A seven-transmembrane, G protein-coupled receptor, FPRL1, mediates the chemotactic activity of serum amyloid A for human phagocytic cells,” Journal of Experimental Medicine, vol. 189, no. 2, pp. 395–402, 1999. View at Publisher · View at Google Scholar · View at Scopus
  30. L. Björkman, J. Karlsson, A. Karlsson et al., “Serum amyloid A mediates human neutrophil production of reactive oxygen species through a receptor independent of formyl peptide receptor like-1,” Journal of Leukocyte Biology, vol. 83, no. 2, pp. 245–253, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. K. Christenson, L. Björkman, C. Tängemo, and J. Bylund, “Serum amyloid A inhibits apoptosis of human neutrophils via a P2X7-sensitive pathway independent of formyl peptide receptor-like 1,” Journal of Leukocyte Biology, vol. 83, no. 1, pp. 139–148, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. B. de Yang, Q. Chen, A. P. Schmidt et al., “LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells,” Journal of Experimental Medicine, vol. 192, no. 7, pp. 1069–1074, 2000. View at Publisher · View at Google Scholar · View at Scopus
  33. D. El Kebir, Y. Zhang, L. A. Potempa, Y. Wu, A. Fournier, and J. G. Filep, “C-reactive protein-derived peptide 201-206 inhibits neutrophil adhesion to endothelial cells and platelets through CD32,” Journal of Leukocyte Biology, vol. 90, no. 6, pp. 1167–1175, 2011. View at Publisher · View at Google Scholar · View at Scopus
  34. V. Aas, K. L. Sand, H. C. Asheim, H. B. Benestad, and J. G. Iversen, “C-reactive protein triggers calcium signalling in human neutrophilic granulocytes via FcgammaRIIa in an allele-specific way,” Scandinavian Journal of Immunology, vol. 77, pp. 442–451, 2013. View at Publisher · View at Google Scholar
  35. J. M. Tadie, H. B. Bae, S. Jiang et al., “HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4,” American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 304, pp. L342–L349, 2013.
  36. M. J. Berridge, “Inositol trisphosphate and calcium signalling mechanisms,” Biochimica et Biophysica Acta, vol. 1793, no. 6, pp. 933–940, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. G. Liu, Y. Bi, R. Wang et al., “Kinase AKT1 negatively controls neutrophil recruitment and function in mice,” Journal of Immunology, vol. 191, no. 5, pp. 2680–2690, 2013. View at Publisher · View at Google Scholar
  38. B. B. Damaj, S. R. McColl, K. Neote, C. A. Heber, and P. H. Naccache, “Diverging signal transduction pathways activated by interleukin 8 (IL- 8) and related chemokines in human neutrophils. IL-8 and Gro-α differentially stimulate calcium influx through IL-8 receptors A and B,” The Journal of Biological Chemistry, vol. 271, no. 34, pp. 20540–20544, 1996. View at Publisher · View at Google Scholar · View at Scopus
  39. M. Mellado, A. Serrano, C. Martínez, and J. M. Rodríguez-Frade, “G protein-coupled receptor dimerization and signaling,” Methods in Molecular Biology, vol. 332, pp. 141–157, 2006. View at Scopus
  40. M. Benkirane, D.-Y. Jin, R. F. Chun, R. A. Koup, and K.-T. Jeang, “Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5Δ32,” The Journal of Biological Chemistry, vol. 272, no. 49, pp. 30603–30606, 1997. View at Publisher · View at Google Scholar · View at Scopus
  41. L. M. Muñoz, P. Lucas, G. Navarro et al., “Dynamic regulation of CXCR1 and CXCR2 homo- and heterodimers,” Journal of Immunology, vol. 183, no. 11, pp. 7337–7346, 2009. View at Publisher · View at Google Scholar · View at Scopus
  42. F. Hüttenrauch, B. Pollok-Kopp, and M. Oppermann, “G protein-coupled receptor kinases promote phosphorylation and β-arrestin-mediated internalization of CCR5 homo- and hetero-oligomers,” The Journal of Biological Chemistry, vol. 280, no. 45, pp. 37503–37515, 2005. View at Publisher · View at Google Scholar · View at Scopus
  43. H. Stockinger, “Interaction of GPI-anchored cell surface proteins and complement receptor type 3,” Experimental and Clinical Immunogenetics, vol. 14, no. 1, pp. 5–10, 1997. View at Scopus
  44. Y. Xia, G. Borland, J. Huang et al., “Function of the lectin domain of Mac-1/complement receptor type 3 (CD11b/CD18) in regulating neutrophil adhesion,” Journal of Immunology, vol. 169, no. 11, pp. 6417–6426, 2002. View at Scopus
  45. H. R. Petty, A. L. Kindzelskii, Y. Adachi, and R. F. Todd III, “Ectodomain interactions of leukocyte integrins and pro-inflammatory GPI-linked membrane proteins,” Journal of Pharmaceutical and Biomedical Analysis, vol. 15, no. 9-10, pp. 1405–1416, 1997. View at Publisher · View at Google Scholar · View at Scopus
  46. H. R. Petty and R. F. Todd III, “Receptor-receptor interactions of complement receptor type 3 in neutrophil membranes,” Journal of Leukocyte Biology, vol. 54, no. 5, pp. 492–494, 1993. View at Scopus
  47. D. A. Finney and L. A. Sklar, “Ligand/receptor internalization: a kinetic, flow cytometric analysis of the internalization of N-formyl peptides by human neutrophils,” Cytometry, vol. 4, no. 1, pp. 54–60, 1983. View at Scopus
  48. L. Marois, E. Rollet-Labelle, and P. H. Naccache, “FcRs on human neutrophils. Emerging patho-physiological concerns,” Advances in Medicine and Biology, vol. 15, no. 48, 2011.
  49. L. Marois, M. Vaillancourt, S. Marois et al., “The ubiquitin ligase c-Cbl down-regulates FcγRIIa activation in human neutrophils,” Journal of Immunology, vol. 182, no. 4, pp. 2374–2384, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. R. Feniger-Barish, M. Ran, A. Zaslaver, and A. Ben-Baruch, “Differential modes of regulation of CXC chemokine-induced internalization and recycling of human CXCR1 and CXCR2,” Cytokine, vol. 11, no. 12, pp. 996–1009, 1999. View at Publisher · View at Google Scholar · View at Scopus
  51. A. Zaslaver, R. Feniger-Barish, and A. Ben-Baruch, “Actin filaments are involved in the regulation of trafficking of two closely related chemokine receptors, CXCR1 and CXCR2,” Journal of Immunology, vol. 166, no. 2, pp. 1272–1284, 2001. View at Scopus
  52. G. N. Prado, H. Suzuki, N. Wilkinson, B. Cousins, and J. Navarro, “Role of the C terminus of the interleukin 8 receptor in signal transduction and internalization,” The Journal of Biological Chemistry, vol. 271, no. 32, pp. 19186–19190, 1996. View at Publisher · View at Google Scholar · View at Scopus
  53. D. Bock, U. Martin, S. Gärtner et al., “The C terminus of the human C5a receptor (CD88) is required for normal ligand-dependent receptor internalization,” European Journal of Immunology, vol. 27, no. 6, pp. 1522–1529, 1997. View at Publisher · View at Google Scholar · View at Scopus
  54. J. F. Hoffman, J. J. Linderman, and G. M. Omann, “Receptor up-regulation, internalization, and interconverting receptor states. Critical components of a quantitative description of N-formyl peptide-receptor dynamics in the neutrophil,” The Journal of Biological Chemistry, vol. 271, no. 31, pp. 18394–18404, 1996. View at Publisher · View at Google Scholar · View at Scopus
  55. J. Barlic, M. H. Khandaker, E. Mahon et al., “β-Arrestins regulate interleukin-8-induced CXCR1 internalization,” The Journal of Biological Chemistry, vol. 274, no. 23, pp. 16287–16294, 1999. View at Publisher · View at Google Scholar · View at Scopus
  56. D. E. van Epps, S. Simpson, J. G. Bender, and D. E. Chenoweth, “Regulation of C5a and formyl peptide receptor expression on human polymorphonuclear leukocytes,” Journal of Immunology, vol. 144, no. 3, pp. 1062–1068, 1990. View at Scopus
  57. E. L. Becker, J. C. Kermode, P. H. Naccache, et al., “The inhibition of neutrophil granule enzyme secretion and chemotaxis by pertussis toxin,” Journal of Cell Biology, vol. 100, no. 5, pp. 1641–1646, 1985.
  58. M. Volpi, P. H. Naccache, and T. F. P. Molski, “Pertussis toxin inhibits fMet-Leu-Phe- but not phorbol ester-stimulated changes in rabbit neutrophils: role of G proteins in excitation response coupling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 82, no. 9, pp. 2708–2712, 1985. View at Scopus
  59. M. W. Verghese, C. D. Smith, and R. Snyderman, “Potential role for a guanine nucleotide regulatory protein in chemoattractant receptor mediated polyphosphoinositide metabolism, Ca+2 mobilization and cellular responses by leukocytes,” Biochemical and Biophysical Research Communications, vol. 127, no. 2, pp. 450–457, 1985. View at Scopus
  60. T. F. P. Molski, P. H. Naccache, M. L. Marsh, J. Kermode, E. L. Becker, and R. I. Sha'afi, “Pertussis toxin inhibits the rise in the intracellular concentration of free calcium that is induced by chemotactic factors in rabbit neutrophils: possible role of the “G proteins” in calcium mobilization,” Biochemical and Biophysical Research Communications, vol. 124, no. 2, pp. 644–650, 1984. View at Scopus
  61. M. Verghese, R. J. Uhing, and R. Snyderman, “A pertussis/choleratoxin-sensitive N protein may mediate chemoattractant receptor signal transduction,” Biochemical and Biophysical Research Communications, vol. 138, no. 2, pp. 887–894, 1986. View at Scopus
  62. B. B. Damaj, S. R. McColl, W. Mahana, M. F. Crouch, and P. H. Naccache, “Physical association of Gi2α with interleukin-8 receptors,” The Journal of Biological Chemistry, vol. 271, no. 22, pp. 12783–12789, 1996. View at Scopus
  63. T. T. Amatruda III, S. Dragas-Graonic, R. Holmes, and H. D. Perez, “Signal transduction by the formyl peptide receptor: studies using chimeric receptors and site-directed mutagenesis define a novel domain for interaction with G-proteins,” The Journal of Biological Chemistry, vol. 270, no. 47, pp. 28010–28013, 1995. View at Publisher · View at Google Scholar · View at Scopus
  64. L. Stephens, A. Smrcka, F. T. Cooke, T. R. Jackson, P. C. Sternweis, and P. T. Hawkins, “A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein βγ subunits,” Cell, vol. 77, no. 1, pp. 83–93, 1994. View at Publisher · View at Google Scholar · View at Scopus
  65. S. Krugmann, P. T. Hawkins, N. Pryer, and S. Braselmann, “Characterizing the interactions between the two subunits of the p101/p110γ/phosphoinositide 3-kinase and their role in the activation of this enzyme by G(βγ) subunits,” The Journal of Biological Chemistry, vol. 274, no. 24, pp. 17152–17158, 1999. View at Publisher · View at Google Scholar · View at Scopus
  66. M. Majeed, E. Caveggion, C. A. Lowell, and G. Berton, “Role of Src kinases and Syk in Fcγ receptor-mediated phagocytosis and phagosome-lysosome fusion,” Journal of Leukocyte Biology, vol. 70, no. 5, pp. 801–811, 2001. View at Scopus
  67. S. R. Yan, M. Huang, and G. Berton, “Signaling by adhesion in human neutrophils: activation of the p72syk tyrosine kinase and formation of protein complexes containing p72syk and Src family kinases in neutrophils spreading over fibrinogen,” Journal of Immunology, vol. 158, no. 4, pp. 1902–1910, 1997. View at Scopus
  68. I. Ibarrola, P. J. M. Vossebeld, C. H. E. Homburg, M. Thelen, D. Roos, and A. J. Verhoeven, “Influence of tyrosine phosphorylation on protein interaction with FcγRIIa,” Biochimica et Biophysica Acta, vol. 1357, no. 3, pp. 348–358, 1997. View at Publisher · View at Google Scholar · View at Scopus
  69. F. Kiefer, J. Brumell, N. Al-Alawi et al., “The Syk protein tyrosine kinase is essential for Fcγ/receptor signaling in macrophages and neutrophils,” Molecular and Cellular Biology, vol. 18, no. 7, pp. 4209–4220, 1998. View at Scopus
  70. L. Fumagalli, H. Zhang, A. Baruzzi, C. A. Lowell, and G. Berton, “The Src family kinases Hck and Fgr regulate neutrophil responses to N-formyl-methionyl-leucyl-phenylalanine,” Journal of Immunology, vol. 178, no. 6, pp. 3874–3885, 2007. View at Scopus
  71. C. Giagulli, L. Ottoboni, E. Caveggion et al., “The Src family kinases Hck and Fgr are dispensable for inside-out, chemoattractant-induced signaling regulating β2 integrin affinity and valency in neutrophils, but are required for β2 integrin-mediated outside-in signaling involved in sustained adhesion,” Journal of Immunology, vol. 177, no. 1, pp. 604–611, 2006. View at Scopus
  72. C. Astarie-Dequeker, S. Carreno, C. Cougoule, and I. Maridonneau-Parini, “The protein tyrosine kinase Hck is located on lysosomal vesicles that are physically and functionally distinct from CD63-positive lysosomes in human macrophages,” Journal of Cell Science, vol. 115, no. 1, pp. 81–89, 2002. View at Scopus
  73. M. J. G. Fernandes, G. Lachance, G. Paré, E. Rollet-Labelle, and P. H. Naccache, “Signaling through CD16b in human neutrophils involves the Tec family of tyrosine kinases,” Journal of Leukocyte Biology, vol. 78, no. 2, pp. 524–532, 2005. View at Publisher · View at Google Scholar · View at Scopus
  74. O. Popa-Nita, E. Rollet-Labelle, N. Thibault, C. Gilbert, S. G. Bourgoin, and P. H. Naccache, “Crystal-induced neutrophil activation. IX. Syk-dependent activation of class Ia phosphatidylinositol 3-kinase,” Journal of Leukocyte Biology, vol. 82, no. 3, pp. 763–773, 2007. View at Publisher · View at Google Scholar · View at Scopus
  75. O. Popa-Nita, L. Marois, G. Paré, and P. H. Naccache, “Crystal-induced neutrophil activation: X. Proinflammatory role of the tyrosine kinase Tec,” Arthritis and Rheumatism, vol. 58, no. 6, pp. 1866–1876, 2008. View at Publisher · View at Google Scholar · View at Scopus
  76. M. Gaudry, C. Gilbert, F. Barabe, P. E. Poubelle, and P. H. Naccache, “Activation of Lyn is a common element of the stimulation of human neutrophils by soluble and particulate agonists,” Blood, vol. 86, no. 9, pp. 3567–3574, 1995. View at Scopus
  77. A. Zarbock and K. Ley, “Protein tyrosine kinases in neutrophil activation and recruitment,” Archives of Biochemistry and Biophysics, vol. 510, no. 2, pp. 112–119, 2011. View at Publisher · View at Google Scholar · View at Scopus
  78. K. Zen and Y. Liu, “Role of different protein tyrosine kinases in fMLP-induced neutrophil transmigration,” Immunobiology, vol. 213, no. 1, pp. 13–23, 2008. View at Publisher · View at Google Scholar · View at Scopus
  79. R. G. Sitrin, S. L. Emery, T. M. Sassanella, R. A. Blackwood, and H. R. Petty, “Selective localization of recognition complexes for leukotriene B4 and formyl-met-leu-phe within lipid raft microdomains of human polymorphonuclear neutrophils,” Journal of Immunology, vol. 177, no. 11, pp. 8177–8184, 2006. View at Scopus
  80. G. Lachance, S. Levasseur, and P. H. Naccache, “Chemotactic factor-induced recruitment and activation of Tec family kinases in human neutrophils. Implication of phosphatidylinositol 3-kinases,” The Journal of Biological Chemistry, vol. 277, no. 24, pp. 21537–21541, 2002. View at Publisher · View at Google Scholar · View at Scopus
  81. C. Gilbert, S. Levasseur, P. Desaulniers et al., “Chemotactic factor-induced recruitment and activation of Tec family kinases in human neutrophils. II. Effects of LFM-A13, a specific Btk inhibitor,” Journal of Immunology, vol. 170, no. 10, pp. 5235–5243, 2003. View at Scopus
  82. P. Desaulniers, M. Fernandes, C. Gilbert, S. G. Bourgoin, and P. H. Naccache, “Crystal-induced neutrophil activation. VII. Involvement of Syk in the responses to monosodium urate crystals,” Journal of Leukocyte Biology, vol. 70, no. 4, pp. 659–668, 2001. View at Scopus
  83. O. Popa-Nita, S. Proulx, G. Paré, E. Rollet-Labelle, and P. H. Naccache, “Crystal-induced neutrophil activation: XI. Implication and novel roles of classical protein kinase C,” Journal of Immunology, vol. 183, no. 3, pp. 2104–2114, 2009. View at Publisher · View at Google Scholar · View at Scopus
  84. A. Kasorn, P. Alcaide, Y. Jia et al., “Focal adhesion kinase regulates pathogen-killing capability and life span of neutrophils via mediating both adhesion-dependent and -independent cellular signals,” Journal of Immunology, vol. 183, no. 2, pp. 1032–1043, 2009. View at Publisher · View at Google Scholar · View at Scopus
  85. H. Tong, B. Zhao, H. Shi et al., “c-Abl tyrosine kinase plays a critical role in beta2 integrin-dependent neutrophil migration by regulating Vav1 activity,” Journal of Leukocyte Biology, vol. 93, pp. 611–622, 2013. View at Publisher · View at Google Scholar
  86. A. Baruzzi, I. Iacobucci, S. Soverini, C. A. Lowell, G. Martinelli, and G. Berton, “c-Abl and Src-family kinases cross-talk in regulation of myeloid cell migration,” FEBS Letters, vol. 584, no. 1, pp. 15–21, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. P. H. Naccache, H. J. Showell, E. L. Becker, and R. I. Sha'afi, “Transport of sodium, potassium, and calcium across rabbit polymorphonuclear leukocyte membranes. Effect of chemotactic factor,” Journal of Cell Biology, vol. 73, no. 2, pp. 428–444, 1977. View at Scopus
  88. R. J. Petroski, P. H. Naccache, E. L. Becker, and R. I. Sha'afi, “Effect of chemotactic factors on calcium levels of rabbit neutrophils,” American Journal of Physiology: Cell Physiology, vol. 6, no. 1, pp. C43–C49, 1979. View at Scopus
  89. J. R. White, P. H. Naccache, T. F. P. Molski, P. Borgeat, and R. I. Sha'afi, “Direct demonstration of increased intracellular concentration of free calcium in rabbit and human neutrophils following stimulation by chemotactic factor,” Biochemical and Biophysical Research Communications, vol. 113, no. 1, pp. 44–50, 1983.
  90. T. Pozzan, D. P. Lew, C. B. Wollheim, and R. Y. Tsien, “Is cytosolic ionized calcium regulating neutrophil activation?” Science, vol. 221, no. 4618, pp. 1413–1415, 1983. View at Scopus
  91. F. V. Davies, A. K. Campbell, and M. B. Hallett, “Ca2+ oscillations in neutrophils triggered by immune complexes result from Ca2+ influx,” Immunology, vol. 82, no. 1, pp. 57–62, 1994. View at Scopus
  92. P. Volpe, K.-H. Krause, S. Hashimoto et al., “‘Calciosome’, a cytoplasmic organelle: the inositol 1,4,5-trisphosphate-sensitive Ca2+ store of nonmuscle cells?” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 4, pp. 1091–1095, 1988. View at Scopus
  93. M. Volpi, R. Yassin, P. H. Naccache, and R. I. Sha'afi, “Chemotactic factor causes rapid decreases in phosphatidyl-inositol,4,5-bisphosphate and phosphatidylinositol 4-monophosphate in rabbit neutrophils,” Biochemical and Biophysical Research Communications, vol. 112, no. 3, pp. 957–964, 1983. View at Scopus
  94. W. M. Mackin, “Effects of GTPγS and fMet-Leu-Phe on rat PMN phospholipase C (PLC) activity,” Agents and Actions, vol. 27, no. 3-4, pp. 407–409, 1989. View at Scopus
  95. J. F. Klinker, K. Wenzel-Seifert, and R. Seifert, “G-Protein-coupled receptors in HL-60 human leukemia cells,” General Pharmacology, vol. 27, no. 1, pp. 33–54, 1996. View at Publisher · View at Google Scholar · View at Scopus
  96. P. H. Naccache, M. M. Molski, and M. Volpi, “Biochemical events associated with the stimulation of rabbit neutrophils by platelet-activating factor,” Journal of Leukocyte Biology, vol. 40, no. 5, pp. 533–548, 1986. View at Scopus
  97. T. T. Amatruda III, S. Dragas-Graonic, R. Holmes, and H. D. Perez, “Signal transduction by the formyl peptide receptor: studies using chimeric receptors and site-directed mutagenesis define a novel domain for interaction with G-proteins,” The Journal of Biological Chemistry, vol. 270, no. 47, pp. 28010–28013, 1995. View at Publisher · View at Google Scholar · View at Scopus
  98. H. Jiang, Y. Kuang, Y. Wu, W. Xie, M. I. Simon, and D. Wu, “Roles of phospholipase C β2 in chemoattractant-elicited responses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 15, pp. 7971–7975, 1997. View at Publisher · View at Google Scholar · View at Scopus
  99. J. I. Wilde and S. P. Watson, “Regulation of phospholipase C γ isoforms in haematopoietic cells—Why one, not the other?” Cellular Signalling, vol. 13, no. 10, pp. 691–701, 2001. View at Publisher · View at Google Scholar · View at Scopus
  100. S. Dusi, M. Donini, V. Della Bianca, and F. Rossi, “Tyrosine phosphorylation of phospholipase C-γ2 is involved in the activation of phosphoinositide hydrolysis by Fc receptors in human neutrophils,” Biochemical and Biophysical Research Communications, vol. 201, no. 3, pp. 1100–1108, 1994. View at Publisher · View at Google Scholar · View at Scopus
  101. C. Hellberg, L. Molony, L. Zheng, and T. Andersson, “Ca2+ signalling mechanisms of the beta 2 integrin on neutrophils: involvement of phospholipase C gamma 2 and Ins(1,4,5)P3,” The Biochemical journal, vol. 317, p. 2, 1996. View at Scopus
  102. K. Kwiatkowska and A. Sobota, “The clustered Fc gamma receptor II is recruited to Lyn-containing membrane domains and undergoes phosphorylation in a cholesterol-dependent manner,” European Journal of Immunology, vol. 31, pp. 989–998, 2001.
  103. K. Kwiatkowska, J. Frey, and A. Sobota, “Phosphorylation of FcγRIIA is required for the receptor-induced actin rearrangement and capping: the role of membrane rafts,” Journal of Cell Science, vol. 116, no. 3, pp. 537–550, 2003. View at Publisher · View at Google Scholar · View at Scopus
  104. C. Gilbert, E. Rollet-Labelle, A. C. Caon, and P. H. Naccache, “Immunoblotting and sequential lysis protocols for the analysis of tyrosine phosphorylation-dependent signaling,” Journal of Immunological Methods, vol. 271, no. 1-2, pp. 185–201, 2002. View at Publisher · View at Google Scholar · View at Scopus
  105. J. T. Smyth, S.-Y. Hwang, T. Tomita, W. I. DeHaven, J. C. Mercer, and J. W. Putney, “Activation and regulation of store-operated calcium entry,” Journal of Cellular and Molecular Medicine, vol. 14, no. 10, pp. 2337–2349, 2010. View at Publisher · View at Google Scholar · View at Scopus
  106. I. Bogeski, T. Kilch, and B. A. Niemeyer, “ROS and SOCE: recent advances and controversies in the regulation of STIM and Orai,” The Journal of Physiology, vol. 590, pp. 4193–4200, 2012. View at Publisher · View at Google Scholar
  107. S. Srikanth and Y. Gwack, “Orai1, STIM1, and their associating partners,” The Journal of Physiology, vol. 590, pp. 4169–4177, 2012. View at Publisher · View at Google Scholar
  108. I. Derler, J. Madl, G. Schütz, and C. Romanin, “Structure, regulation and biophysics of ICRAC, STIM/Orai1,” Advances in Experimental Medicine and Biology, vol. 740, pp. 383–410, 2012. View at Publisher · View at Google Scholar · View at Scopus
  109. A. Berna-Erro, P. C. Redondo, and J. A. Rosado, “Store-operated Ca2+ entry,” Advances in Experimental Medicine and Biology, vol. 740, pp. 349–382, 2012. View at Publisher · View at Google Scholar · View at Scopus
  110. L. Marois, G. Paré, M. Vaillancourt, E. Rollet-Labelle, and P. H. Naccache, “FcγRIIIb triggers raft-dependent calcium influx in IgG-mediated responses in human neutrophils,” The Journal of Biological Chemistry, vol. 286, no. 5, pp. 3509–3519, 2011. View at Publisher · View at Google Scholar · View at Scopus
  111. M. D. Salmon and J. Ahluwalia, “Pharmacology of receptor operated calcium entry in human neutrophils,” International Immunopharmacology, vol. 11, no. 2, pp. 145–148, 2011. View at Publisher · View at Google Scholar · View at Scopus
  112. M. D. Salmon and J. Ahluwalia, “Discrimination between receptor- and store-operated Ca2+ influx in human neutrophils,” Cellular Immunology, vol. 265, no. 1, pp. 1–5, 2010. View at Publisher · View at Google Scholar · View at Scopus
  113. C. Cai, S. Tang, X. Wang et al., “Requirement for both receptor-operated and store-operated calcium entry in N-formyl-methionine-leucine-phenylalanine-induced neutrophil polarization,” Biochemical and Biophysical Research Communications, vol. 430, pp. 816–821, 2013. View at Publisher · View at Google Scholar
  114. W. Zou, X. Meng, C. Cai et al., “Store-operated Ca2+ entry (SOCE) plays a role in the polarization of neutrophil-like HL-60 cells by regulating the activation of Akt, Src, and Rho family GTPases,” Cell Physiol Biochem, vol. 30, pp. 221–237, 2012. View at Publisher · View at Google Scholar
  115. T. J. Shuttleworth, J. L. Thompson, and O. Mignen, “STIM1 and the noncapacitative ARC channels,” Cell Calcium, vol. 42, no. 2, pp. 183–191, 2007. View at Publisher · View at Google Scholar · View at Scopus
  116. I. Heiner, J. Eisfeld, C. R. Halaszovich et al., “Expression profile of the transient receptor potential (TRP) family in neutrophil granulocytes: evidence for currents through long TRP channel 2 induced by ADP-ribose and NAD,” Biochemical Journal, vol. 371, no. 3, pp. 1045–1053, 2003. View at Publisher · View at Google Scholar · View at Scopus
  117. I. Heiner, J. Eisfeld, M. Warnstedt, N. Radukina, E. Jüngling, and A. Lückhoff, “Endogenous ADP-ribose enables calcium-regulated cation currents through TRPM2 channels in neutrophil granulocytes,” Biochemical Journal, vol. 398, no. 2, pp. 225–232, 2006. View at Publisher · View at Google Scholar · View at Scopus
  118. E. Pantaler and A. Lückhoff, “Inhibitors of TRP channels reveal stimulus-dependent differential activation of Ca2+ influx pathways in human neutrophil granulocytes,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 380, no. 6, pp. 497–507, 2009. View at Publisher · View at Google Scholar · View at Scopus
  119. L. Zeng, S. V. Webster, and P. M. Newton, “The biology of protein kinase C,” Advances in Experimental Medicine and Biology, vol. 740, pp. 639–661, 2012. View at Publisher · View at Google Scholar · View at Scopus
  120. A. C. Newton, “Protein kinase C: poised to signal,” American Journal of Physiology: Endocrinology and Metabolism, vol. 298, no. 3, pp. E395–E402, 2010. View at Publisher · View at Google Scholar · View at Scopus
  121. M. Castagna, Y. Takai, and K. Kaibuchi, “Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters,” The Journal of Biological Chemistry, vol. 257, no. 13, pp. 7847–7851, 1982. View at Scopus
  122. L.-T. Tsao and J.-P. Wang, “Translocation of protein kinase C isoforms in rat neutrophils,” Biochemical and Biophysical Research Communications, vol. 234, no. 2, pp. 412–418, 1997. View at Publisher · View at Google Scholar · View at Scopus
  123. J. E. Repine, J. G. White, C. C. Clawson, and B. M. Holmes, “Effects of phorbol myristate acetate on the metabolism and ultrastructure of neutrophils in chronic granulomatous disease,” Journal of Clinical Investigation, vol. 54, no. 1, pp. 83–90, 1974. View at Scopus
  124. J. E. Repine, J. G. White, C. C. Clawson, and B. M. Holmes, “The influence of phorbol myristate acetate on oxygen consumption by polymorphonuclear leukocytes,” Journal of Laboratory and Clinical Medicine, vol. 83, no. 6, pp. 911–920, 1974. View at Scopus
  125. J. G. White and R. D. Estensen, “Selective labilization of specific granules in polymorphonuclear leukocytes by phorbol myristate acetate,” American Journal of Pathology, vol. 75, no. 1, pp. 45–54, 1974. View at Scopus
  126. L. R. de Chatelet, P. S. Shirley, and R. B. Johnston Jr., “Effect of phorbol myristate acetate on the oxidative metabolism of human polymorphonuclear leukocytes,” Blood, vol. 47, no. 4, pp. 545–554, 1976. View at Scopus
  127. J. El-Benna, P. M.-C. Dang, M.-A. Gougerot-Pocidalo, J.-C. Marie, and F. Braut-Boucher, “p47phox, the phagocyte NADPH oxidase/NOX2 organizer: structure, phosphorylation and implication in diseases,” Experimental and Molecular Medicine, vol. 41, no. 4, pp. 217–225, 2009. View at Publisher · View at Google Scholar · View at Scopus
  128. R. I. Sha'afi, J. R. White, and T. F. P. Molski, “Phorbol 12-myristate 13-acetate activates rabbit neutrophils without an apparent rise in the level of intracellular free calcium,” Biochemical and Biophysical Research Communications, vol. 114, no. 2, pp. 638–645, 1983. View at Scopus
  129. C. Gilbert, M. Gaudry, and P. H. Naccache, “Rapid priming of calcium mobilization and superoxide anion production in human neutrophils by substimulatory concentrations of phorbol esters: a novel role for protein kinase C and tyrosine phosphorylation in the up-modulation of signal transduction,” Cellular Signalling, vol. 4, no. 5, pp. 511–523, 1992. View at Publisher · View at Google Scholar · View at Scopus
  130. P. H. Naccache, T. F. P. Molski, P. Borgeat, and R. I. Sha'afi, “Phorbol esters inhibit the fMet-Leu-Phe- and leukotriene B4-stimulated calcium mobilization and enzyme secretion in rabbit neutrophils,” The Journal of Biological Chemistry, vol. 260, no. 4, pp. 2125–2131, 1985. View at Scopus
  131. T. Matsumoto, T. F. P. Molski, M. Volpi, et al., “Treatment of rabbit neutrophils with phorbol esters results in increased ADP-ribosylation catalyzed by pertussis toxin and inhibition of the GTPase stimulated by fMet-Leu-Phe,” FEBS Letters, vol. 198, no. 2, pp. 295–300, 1986. View at Scopus
  132. A. Al-Shami, S. G. Bourgoin, and P. H. Naccache, “Granulocyte-macrophage colony-stimulating factor-activated signaling pathways in human neutrophils. I. Tyrosine phosphorylation-dependent stimulation of phosphatidylinositol 3-kinase and inhibition by phorbol esters,” Blood, vol. 89, no. 3, pp. 1035–1044, 1997. View at Scopus
  133. C. Salerno and E. Capuozzo, “Effects of the semisynthetic bis-indole derivative KAR-2 on store-operated calcium entry in human neutrophils,” Arch Biochem Biophys, 2013.
  134. F. S. Lakschevitz, G. M. Aboodi, and M. Glogauer, “Oral neutrophil transcriptome changes result in a pro-survival phenotype in periodontal diseases,” PLoS One, vol. 8, Article ID e68983, 2013.
  135. W. S. Maaty, C. I. Lord, J. M. Gripentrog et al., “Identification of C-terminal phosphorylation sites of N-formyl peptide receptor-1 (FPR1) in human blood neutrophils,” The Journal of Biological Chemistry, vol. 288, pp. 27042–27058, 2013.
  136. S. Casulli and C. Elbim, “Interactions between human immunodeficiency virus type 1 and polymorphonuclear neutrophils,” Journal of Innate Immunity, Article ID 23867213, 2013. View at Publisher · View at Google Scholar
  137. O. Lindemann, D. Umlauf, S. Frank et al., “TRPC6 regulates CXCR2-mediated chemotaxis of murine neutrophils,” Journal of Immunology, vol. 190, pp. 5496–5505, 2013. View at Publisher · View at Google Scholar
  138. R. Chari, S. Kim, S. Murugappan, A. Sanjay, J. L. Daniel, and S. P. Kunapuli, “Lyn, PKC-δ, SHIP-1 interactions regulate GPVI-mediated platelet-dense granule secretion,” Blood, vol. 114, no. 14, pp. 3056–3063, 2009. View at Publisher · View at Google Scholar · View at Scopus
  139. S. Andrews, L. R. Stephens, and P. T. Hawkins, “PI3K class IB pathway in neutrophils,” Science's STKE : signal transduction knowledge environment, vol. 2007, no. 407, p. cm3, 2007. View at Publisher · View at Google Scholar · View at Scopus
  140. P. T. Hawkins, K. E. Anderson, K. Davidson, and L. R. Stephens, “Signalling through Class I PI3Ks in mammalian cells,” Biochemical Society Transactions, vol. 34, no. 5, pp. 647–662, 2006. View at Publisher · View at Google Scholar · View at Scopus
  141. L. R. Stephens, K. T. Hughes, and R. F. Irvine, “Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils,” Nature, vol. 351, no. 6321, pp. 33–39, 1991. View at Publisher · View at Google Scholar · View at Scopus
  142. A. E. Traynor-Kaplan, B. L. Thompson, A. L. Harris, P. G. M. Taylor Omann, and L. A. Sklar, “Transient increase in phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol trisphosphate during activation of human neutrophils,” The Journal of Biological Chemistry, vol. 264, no. 26, pp. 15668–15673, 1989. View at Scopus
  143. M. Vaillancourt, S. Levasseur, M.-L. Tremblay, L. Marois, E. Rollet-Labelle, and P. H. Naccache, “The Src homology 2-containing inositol 5-phosphatase 1 (SHIP1) is involved in CD32a signaling in human neutrophils,” Cellular Signalling, vol. 18, no. 11, pp. 2022–2032, 2006. View at Publisher · View at Google Scholar · View at Scopus
  144. P. H. Naccache, S. Levasseur, G. Lachance, S. Chakravarti, S. G. Bourgoini, and S. R. McColl, “Stimulation of human neutrophils by chemotactic factors is associated with the activation of phosphatidylinositol 3-kinase γ,” The Journal of Biological Chemistry, vol. 275, no. 31, pp. 23636–23641, 2000. View at Publisher · View at Google Scholar · View at Scopus
  145. L. R. Stephens, A. Eguinoa, H. Erdjument-Bromage et al., “The Gβγ/sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101,” Cell, vol. 89, no. 1, pp. 105–114, 1997. View at Scopus
  146. S. Suire, A. M. Condliffe, G. J. Ferguson et al., “Gβγs and the Ras binding domain of p110γ are both important regulators of PI3Kγ signalling in neutrophils,” Nature Cell Biology, vol. 8, no. 11, pp. 1303–1309, 2006. View at Publisher · View at Google Scholar · View at Scopus
  147. Z. Jakus, S. Fodor, C. L. Abram, C. A. Lowell, and A. Mócsai, “Immunoreceptor-like signaling by β2 and β3 integrins,” Trends in Cell Biology, vol. 17, no. 10, pp. 493–501, 2007. View at Publisher · View at Google Scholar · View at Scopus
  148. Z. Li, H. Jiang, W. Xie, Z. Zhang, A. V. Smrcka, and D. Wu, “Roles of PLC-β2 and -β3 and PI3kγ in chemoattractant-mediated signal transduction,” Science, vol. 287, no. 5455, pp. 1046–1049, 2000. View at Publisher · View at Google Scholar · View at Scopus
  149. E. Hirsch, V. L. Katanaev, C. Garlanda et al., “Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation,” Science, vol. 287, no. 5455, pp. 1049–1052, 2000. View at Publisher · View at Google Scholar · View at Scopus
  150. T. Sasaki, J. Irie-Sasaki, R. G. Jones et al., “Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration,” Science, vol. 287, no. 5455, pp. 1040–4046, 2000. View at Publisher · View at Google Scholar · View at Scopus
  151. I. Boulven, S. Levasseur, S. Marois, G. Paré, E. Rollet-Labelle, and P. H. Naccache, “Class IA phosphatidylinositide 3-kinases, rather than p110γ, regulate formyl-methionyl-leucyl-phenylalanine-stimulated chemotaxis and superoxide production in differentiated neutrophil-like PLB-985 cells,” Journal of Immunology, vol. 176, no. 12, pp. 7621–7627, 2006. View at Scopus
  152. J. G. R. Elferink and B. M. de Koster, “The effect of cyclic GMP and cyclic AMP on migration by electroporatedf human neutrophils,” European Journal of Pharmacology, vol. 246, no. 2, pp. 157–161, 1993. View at Publisher · View at Google Scholar · View at Scopus
  153. S. Zalavary, O. Stendahl, and T. Bengtsson, “The role of cyclic AMP, calcium and filamentous actin in adenosine modulation of FC receptor-mediated phagocytosis in human neutrophils,” Biochimica et Biophysica Acta, vol. 1222, no. 2, pp. 249–256, 1994. View at Publisher · View at Google Scholar · View at Scopus
  154. M. U. Ahmed, K. Hazeki, O. Hazeki, T. Katada, and M. Ui, “Cyclic AMP-increasing agents interfere with chemoattractant-induced respiratory burst in neutrophils as a result of the inhibition of phosphatidylinositol 3-kinase rather than receptor-operated Ca2+ influx,” The Journal of Biological Chemistry, vol. 270, no. 40, pp. 23816–23822, 1995. View at Publisher · View at Google Scholar · View at Scopus
  155. L. Ottonello, M. P. Morone, P. Dapino, and F. Dallegri, “Cyclic AMP-elevating agents down-regulate the oxidative burst induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) in adherent neutrophils,” Clinical and Experimental Immunology, vol. 101, no. 3, pp. 502–506, 1995. View at Scopus
  156. R. Anderson, A. G. Mahomed, A. J. Theron, G. Ramafi, and C. Feldman, “Effect of rolipram and dibutyryl cyclic AMP on resequestration of cytosolic calcium in FMLP-activated human neutrophils,” British Journal of Pharmacology, vol. 124, no. 3, pp. 547–555, 1998. View at Publisher · View at Google Scholar · View at Scopus
  157. L. Ottonello, R. Gonella, P. Dapino, C. Sacchetti, and F. Dallegri, “Prostaglandin E2 inhibits apoptosis in human neutrophilic polymorphonuclear leukocytes: role of intracellular cyclic AMP levels,” Experimental Hematology, vol. 26, no. 9, pp. 895–902, 1998. View at Scopus
  158. J. G. R. Elferink and B. M. de Koster, “Inhibition of interleukin-8-activated human neutrophil chemotaxis by thapsigargin in a calcium-and cyclic AMP-dependent way,” Biochemical Pharmacology, vol. 59, no. 4, pp. 369–375, 2000. View at Publisher · View at Google Scholar · View at Scopus
  159. N. Thibault, C. Burelout, D. Harbour, P. Borgeat, P. H. Naccache, and S. G. Bourgoin, “Occupancy of adenosine A2a receptors promotes fMLP-induced cyclic AMP accumulation in human neutrophils: impact on phospholipase D activity and recruitment of small GTPases to membranes,” Journal of Leukocyte Biology, vol. 71, no. 2, pp. 367–377, 2002. View at Scopus
  160. S. Jackowski and R. I. Shaafi, “Response of adenosine cyclic 3',5'-monophosphate level in rabbit neutrophils to the chemotactic formyl-methionyl-leucyl-phenylalanine,” Molecular Pharmacology, vol. 16, no. 2, pp. 473–481, 1979. View at Scopus
  161. K. Boonnak, B. M. Slike, G. C. Donofrio, and M. A. Marovich, “Human FcγRII cytoplasmic domains differentially influence antibody-mediated dengue virus infection,” Journal of Immunology, vol. 190, pp. 5659–5665, 2013. View at Publisher · View at Google Scholar
  162. B. Markman, J. J. Tao, and M. Scaltriti, “PI3K pathway inhibitors: better not left alone,” Current Pharmaceutical Design, vol. 19, pp. 895–906, 2013. View at Publisher · View at Google Scholar
  163. M. A. Iannone, G. Wolberg, and T. P. Zimmerman, “Ca2+ ionophore-induced cyclic adenosine-3',5'-monophosphate elevation in human neutrophils. A calmodulin-dependent potentiation of adenylate cyclase response to endogenously produced adenosine: comparison to chemotactic agents,” Biochemical Pharmacology, vol. 42, pp. S105–S111, 1991. View at Publisher · View at Google Scholar · View at Scopus
  164. J. A. Brzostowski, S. Sawai, O. Rozov et al., “Phosphorylation of chemoattractant receptors regulates chemotaxis, actin re-organization, and signal-relay,” Journal of Cell Science, 2013. View at Publisher · View at Google Scholar
  165. M. R. Galdiero, E. Bonavita, I. Barajon, C. Garlanda, A. Mantovani, and S. Jaillon, “Tumor associated macrophages and neutrophils in cancer,” Immunobiology, vol. 218, no. 11, pp. 1402–1410, 2013.
  166. B. K. Pliyev, A. V. Shepelev, and A. V. Ivanova, “Role of the adhesion molecule CD99 in platelet-neutrophil interactions,” European Journal of Haematology, 2013. View at Publisher · View at Google Scholar
  167. Z. Hazan-Eitan, Y. Weinstein, N. Hadad, A. Konforty, and R. Levy, “Induction of FcγRIIA expression in myeloid PLB cells during differentiation depends on cytosolic phospholipase A2 activity and is regulated via activation of CREB by PGE2,” Blood, vol. 108, no. 5, pp. 1758–1766, 2006. View at Publisher · View at Google Scholar · View at Scopus
  168. T. Z. Mayer, F. A. Simard, A. Cloutier, H. Vardhan, C. M. Dubois, and P. P. McDonald, “The p38-MSK1 signaling cascade influences cytokine production through CREB and C/EBP factors in human neutrophils,” Journal of Immunology, 2013. View at Publisher · View at Google Scholar
  169. R. Fritsch, I. de Krijger, K. Fritsch et al., “RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms,” Cell, vol. 153, pp. 1050–1063, 2013. View at Publisher · View at Google Scholar
  170. R. G. Coffey, J. S. Davis, and J. Y. Djeu, “Stimulation of guanylate cyclase activity and reduction of adenylate cyclase activity by granulocyte-macrophage colony-stimulating factor in human blood neutrophils,” Journal of Immunology, vol. 140, no. 8, pp. 2695–2701, 1988. View at Scopus
  171. C. Engdahl, C. Lindholm, A. Stubelius, C. Ohlsson, H. Carlsten, and M. K. Lagerquist, “Periarticular bone loss in antigen-induced arthritis,” Arthritis Rheum, 2013.
  172. M. Kaur and D. Singh, “Neutrophil chemotaxis caused by COPD alveolar macrophages, the role of CXCL8 and the receptors CXCR1 / CXCR2,” Journal of Pharmacology and Experimental Therapeutics, 2013.
  173. A. Mantovani, “The Yin-Yang of Tumor-Associated Neutrophils,” Cancer Cell, vol. 16, no. 3, pp. 173–174, 2009. View at Publisher · View at Google Scholar · View at Scopus
  174. M. T. Silva, M. Correia-Neves, Neutrophils, and Macrophages:, “the main partners of phagocyte cell systems,” Frontiers in Immunology, vol. 3, article 174, 2012. View at Publisher · View at Google Scholar
  175. B. McDonald and P. Kubes, “Cellular and molecular choreography of neutrophil recruitment to sites of sterile inflammation,” Journal of Molecular Medicine, vol. 89, no. 11, pp. 1079–1088, 2011. View at Publisher · View at Google Scholar · View at Scopus
  176. O. Soehnlein and L. Lindbom, “Phagocyte partnership during the onset and resolution of inflammation,” Nature Reviews Immunology, vol. 10, no. 6, pp. 427–439, 2010. View at Publisher · View at Google Scholar · View at Scopus
  177. M. Simons and G. Raposo, “Exosomes—vesicular carriers for intercellular communication,” Current Opinion in Cell Biology, vol. 21, no. 4, pp. 575–581, 2009. View at Publisher · View at Google Scholar · View at Scopus