Mediators of Inflammation

PDF
Mediators of Inflammation / 2012 / Article
Special Issue

Macrophage-Mediated Inflammatory Disorders

View this Special Issue

Review Article | Open Access

Volume 2012 |Article ID 951390 | 15 pages | https://doi.org/10.1155/2012/951390

Tissues Use Resident Dendritic Cells and Macrophages to Maintain Homeostasis and to Regain Homeostasis upon Tissue Injury: The Immunoregulatory Role of Changing Tissue Environments

Maciej Lech,1 Regina Gröbmayr,1 Marc Weidenbusch,1 and Hans-Joachim Anders 1

1Medizinische Klinik und Poliklinik IV, Klinikum der Universität München (LMU), Ziemssenstrasse 1, 80336 München, Germany

Academic Editor: Chiou-Feng Lin
Received14 Sep 2012
Accepted25 Oct 2012
Published03 Dec 2012

Abstract

Most tissues harbor resident mononuclear phagocytes, that is, dendritic cells and macrophages. A classification that sufficiently covers their phenotypic heterogeneity and plasticity during homeostasis and disease does not yet exist because cell culture-based phenotypes often do not match those found in vivo. The plasticity of mononuclear phagocytes becomes obvious during dynamic or complex disease processes. Different data interpretation also originates from different conceptual perspectives. An immune-centric view assumes that a particular priming of phagocytes then causes a particular type of pathology in target tissues, conceptually similar to antigen-specific T-cell priming. A tissue-centric view assumes that changing tissue microenvironments shape the phenotypes of their resident and infiltrating mononuclear phagocytes to fulfill the tissue's need to maintain or regain homeostasis. Here we discuss the latter concept, for example, why different organs host different types of mononuclear phagocytes during homeostasis. We further discuss how injuries alter tissue environments and how this primes mononuclear phagocytes to enforce this particular environment, for example, to support host defense and pathogen clearance, to support the resolution of inflammation, to support epithelial and mesenchymal healing, and to support the resolution of fibrosis to the smallest possible scar. Thus, organ- and disease phase-specific microenvironments determine macrophage and dendritic cell heterogeneity in a temporal and spatial manner, which assures their support to maintain and regain homeostasis in whatever condition. Mononuclear phagocytes contributions to tissue pathologies relate to their central roles in orchestrating all stages of host defense and wound healing, which often become maladaptive processes, especially in sterile and/or diffuse tissue injuries.

1. Introduction

Mononuclear phagocytes are a group of phenotypic distinct members, often referred to as either macrophages or dendritic cells (DC), that derive from myeloid precursors and that contribute to the functions of peripheral tissues [1]. During the last decades, research has focused on the cell-type-specific properties of these cells in culture, which then led to an immunocentric view of their role in disease like if they were primed like T cells to infiltrate target organs to cause tissue damage and drive progressive scaring [2, 3]. A more tissue-centric view of these processes, claiming that the tissues define phenotype and function of resident and infiltrating immune cells to meet tissues needs during homeostasis and disease, seems provocative [4, 5]. In this paper we apply the tissue-centric perspective to discuss the role of resident and infiltrating macrophages and dendritic cells in different organs. We examine tissue needs to maintain homeostasis and how to regain homeostasis upon tissue injury. Furthermore, we discuss how published data supports the view that changing tissue environments induce the well-known different phenotypes of mononuclear phagocytes, a process that not only enforces each of the different environments but also explains the contribution of these cells to the different tissue pathologies. This slightly different perspective may somewhat shape our understanding of macrophage heterogeneity and tissue pathology but certainly also raise new questions for future research.

2. Tissues Need Mononuclear Phagocytes to Maintain Homeostasis

All solid organs and most other tissues harbor a network of DC or macrophages (Table 1). Due to their considerable plasticity and heterogeneity, the tissue-based DC and macrophage populations have been defined as mononuclear phagocytes [1, 6, 7]. These cells provide several important physiological functions during homeostasis (Figure 1). For example, organs like the lung and the liver are exposed to pathogen components from the air or from the gut barrier, respectively, which explains the predominance of a macrophage phenotype that has a higher capacity for phagocytic clearance of pathogen components. The same applies to the bone marrow that requires macrophages for the clearance of the nuclei that get expelled from erythroblasts during their maturation towards erythrocytes [8]. In contrast, the gut mucosa hosts dendritic cells that turn signals from the intestinal flora into the secretion of mitogenic mediators that assist in maintaining an intact epithelial lining of the gut as an important component of the intestinal barrier function [2]. Sterile organs rather harbor dendritic cells. During homeostasis, dendritic cells are sensors and guardians of peripheral tolerance due to their capacity to process self-antigens and signal tolerance to the T-cell pool upon evading the peripheral organs via the lymphatics to reach regional lymph nodes [9]. This functional property constantly assures the quiescence of the immune system in homeostasis. Dendritic cells share certain functions with tissue macrophages such as particle phagocytosis and danger recognition/signaling upon the recognition of pathogens, hence these cells taken together are now referred to as the mononuclear phagocyte system.

TissueMacrophagesDendritic cells
SkinDermal macrophages [10] Dermal DCs, Langerhans cells [10]
BoneOsteoclasts [10] 
Bone marrowBone marrow macrophages [11] 
Ovary/testisOvarian macrophages [12] 
Kidney Interstitial DCs [7, 13]
Pancreas Dendritic cell precursors [14]
SpleenMarginal zone macrophages, red pulp macrophages [10]iDCs, follicular DCs [15]
LiverKupffer cells [10]Plasmacytoid DCs, cDCs [16]
ColonIntestinal macrophages [17]Lamina propria DCs [17]
IleumIntestinal macrophages [17]Lamina propria DCs [17]
StomachIntestinal macrophages [17]Lamina propria DCs [17]
LungAlveolar macrophages [10] 
BrainMicroglia [10] 
DCs: dendritic cells.
Table 1 
Resident mononuclear phagocytes in various organs and tissues.

Figure 1 
Roles of resident dendritic cells and tissue macrophages in homeostasis and disease. AG: antigen; LN: lymph nodes.

3. Tissues Need Mononuclear Phagocytes to Fight Threats to Homeostasis

Tissue injury can be traumatic, infectious, toxic, ischemic, or autoimmune to which the tissue responds by a set of evolutionary conserved danger response programs (Figure 2) [18]. Traumatic injury usually involves vascular injury, which immediately activates clotting to control the danger of potentially fatal bleeding. Inflammation is the second danger response program that is needed to avoid pathogen entry to control infections [2]. Pathogens release pathogen-associated molecular patterns (PAMPs), and damaged tissue cells release damage-associated molecular patterns (DAMPs). PAMPs and DAMPs have an identical capacity to ligate Toll-like receptors (TLR) and other pattern recognition receptors on immune and nonimmune cells in the tissue to secrete proinflammatory cytokines and chemokines [19–21] (Figure 2). DAMPs may originate from intracellular sources that get released by cell necrosis, such as histones [22], HMBG1 [23], ATP [24], or uric acid [25]. Furthermore, proinflammatory macrophages release matrix metalloproteinases (MMPs) and hyaluronidase that digest extracellular matrix (ECM) proteins and thereby reduce the ECM viscosity. This process, together with increased vascular permeability, induces tissue swelling, promotes leukocyte migration, and increases the accessibility of surface receptors to their PAMP and DAMP agonists, that is, inflammation. It is of note that ECM digestion produces small ECM peptides and glycosaminoglycans, which can turn into immunostimulatory DAMPs that enhance the local proinflammatory microenvironment [26]. Tamm-Horsfall protein/uromodulin is another example for a compartment-specific DAMP. It is exclusively secreted at the luminal membrane of distal tubular epithelial cells into the urinary compartment of the tubular lumen. During tubular injury, it may lack into the renal interstitium, where it has the capacity to activate intarenal mononuclear phagocytes via TLR4 and the NLRP3 inflammasome [27, 28]. This way, traumatic and infectious injuries induce a PAMP- and DAMP-rich tissue environment that gets reenforced by dendritic cell and macrophage activation (Figures 2 and 3) [29, 30]. Activation of innate immunity subsequently involves the recruitment of additional leukocytes from the circulation including monocytes as well as IFN-γ-secreting NK cells to the injured tissue. When, upon arrival, the infiltrating macrophages get exposed to the PAMP- and/or DAMP-rich environment, hence, this will lead to their full activation towards the proinflammatory macrophage phenotype [20, 31–33]. Polarization to classically activated macrophages requires interferon-related factor (IRF)5 [34]. Such macrophages secrete IL-1, IL-12, IL-23, TNF-α, and ROS and induce iNOS, , and IL1-R, an expression profile that was classified as “M1” classically activated macrophage by in vitro stimulation with IFN-γ, TNF-α, LPS, or GM-CSF [31]. Polarization towards this bactericidal macrophage type provides the tissue with efficient support for local host defense against pathogens. This potentially life-saving effector functions outweigh the unspecific toxicity of the secreted mediators that can cause significant immunopathology and even transient organ dysfunction (Figure 2) [31, 35].


Figure 2 
Tissue microenvironments and predominant macrophage phenotypes. Danger control involves several response programs that operate from seconds to months after injury. In each of these phases, the tissue environment shapes the phenotype of resident and infiltrating mononuclear phagocytes, which then enforce the particular environment in a feed-forward loop. Their potential to amplify inflammation, healing, or scaring has consequences on the tissue that may be beneficial or unfortunate in terms of rapidly regaining homeostasis and full function of the organ. This illustrates that the evolutionary programs of danger control are not perfect in all settings, but the fact that they were positively selected during evolution allows only one interpretation: they obviously represented the best compromise between the different needs of multicellular organisms. Where these programs cause malfunction, also mononuclear phagocytes contribute to the “disease” process. TLR: Toll-like receptor, ROS: reactive oxygen species, and ECM: extracellular matrix.

Figure 3 
Macrophages in different phases of solid organ pathologies.

The danger response program of classically-activated mononuclear phagocyte-driven tissue inflammation for host defense remained evolutionally conserved in sterile solid organ injuries [36–38]. However, DAMP-driven proinflammatory macrophage effects are not needed to kill pathogens and mostly cause unnecessary immunopathology (“collateral damage”). In DAMP-rich but pathogen-free sterile inflammation (ischemic, toxic, or autoimmune injuries), however, this otherwise beneficial response turns into a maladaptive process, with immunopathology that is not balanced by any significant benefit for the tissue [39]. In sterile injuries, the inflammatory phase can be short-lasting, for example, after a transient insult such as a transient ischemia or toxin exposure (Figure 4) [40]. By contrast, inflammation persists upon repetitive or ongoing ischemia or toxin exposure. For example, proton pump inhibitors accelerate gastric and duodenal ulcer healing, also because they reduce persistent acidic damage of the gastric or duodenal mucosa, a process that is required for the resolution of the inflammatory response and for the completion of the wound healing process [41]. As another example, fetal dermal wound healing takes place in a sterile environment without PAMP exposure to the wound. Therefore, much less proinflammatory macrophages are recruited to the site of injury, which, together with the higher regenerative capacity of fetal tissues, explains why fetal wounds heal faster and without scaring [42]. During the early phase of injury, proinflammatory macrophages are entirely dispensable in sterile wounds as their depletion limits the inflammatory response and fastens the healing process [43]. That is why sterile (PAMP-free) wound care is a validated therapeutic strategy to limit the inflammatory response and to enforce healing of surgical wounds or other skin injuries [44]. In addition, in wounds with vascular lesions and subcutaneous bleeding, erythrocyte-derived iron serves as a DAMP that induces the inflammatory macrophage phenotype, which then again suppresses the wound healing process [45, 46].


Figure 4 
Translating the paradigm of classically activated (M1) and alternatively activated (M2) macrophage into clinical contexts. Classically activated (M1) macrophages promote tissue inflammation and immunopathology based on their role in host defense against intracellular pathogens. Extracellular pathogens are mostly attached by humoral factors such as complement, but when they persist, alternatively activated (M2) macrophages provide means of host defence that involve anti-inflammatory, progenerative, and profibrotic elements. The balance of inflammation and fibrosis varies over time and is different in different disease states and often operates in parallel. For this reasons tissue biopsies often become difficult to read and display a mixture of all these elements. The figure provides examples of common disease entities to illustrate how changing tissue environments involve M1- and M2-macrophages-mediated pathology either in a sequential manner, in an intermittent manner, or in a parallel manner, which largely depends on the associated underlying disease processes and cofactors. We propose that the sequential pattern shown at the top was the one that dominated during the evolution of wound healing from the stage of the first multicellular organisms, for example, healing of mechanical trauma in nonsterile environments. We further propose that all other mixtures that doctors often get to see in pathology textbooks and in their clinics originate from that and represent maladaptive variants of this underlying danger response program that was otherwise extremely successful during evolution.

The uselessness of inflammation in sterile injuries provides the rationale for anti-inflammatory and immunosuppressive treatments. For example, inhibiting the recruitment or activation of proinflammatory mononuclear phagocytes drastically reduces immunopathology and organ malfunction in acute and chronic tissue injuries, for example, in a variety of kidney diseases such as in anti-GBM glomerulonephritis [47], lupus nephritis [48–53], antigen-induced immune complex glomerulonephritis [54], renal allograft injury [55], ischemia reperfusion injury [40, 56–58], and adriamycin nephropathy [59]. In addition, environmental factors can aggravate tissue injury by activating mononuclear phagocytes towards a classically activated phenotype [60]. These can be circulating PAMPs, for example, during transient infections (Figures 2 and 4), vaccines or other drugs with distinct immunostimulatory properties. For example, the chemokine antagonists Met-RANTES and AOP-RANTES block monocyte recruitment but still activate resident tissue macrophages, which is sufficient to aggravate preexisting immune complex glomerulonephritis [54]. In contrast, chemokine antagonists without this immunostimulatory side effect were shown to substantially reduce the related immunopathology in multiple disease models of the kidney [61, 62], the CNS [63, 64], the liver, and other noninfectious types of solid organ inflammation as listed in Figure 3.

Dendritic cells support host defense by rather leaving the tissue via the lymphatics to carry foreign antigens to the regional lymph node, which then trigger antigen-specific immune responses and the influx of antigen-specific effector cells that contribute to tissue inflammation. The PAMP-driven innate immunity strongly activates this process in an adjuvant-like manner. Hence, PAMP exposure, for example, during transient infections, can induce the onset or flares of subclinical or chronic autoimmune disorders (Figure 4) [49–54, 65–69].

Together, injuries change the homeostatic tissue towards DAMP- and or PAMP-rich environments which activate resident and infiltrating mononuclear phagocytes. These produce additional immunostimulatory mediators that setup local inflammation, a process that is evolutionally conserved to control invading pathogens. This danger response program is often associated with significant immunopathology, especially in sterile inflammation. This causes unnecessary tissue injury and becomes a maladaptive disease pathomechanism, which provides the rationale for immunosuppressive and anti-inflammatory therapies.

4. Tissues Need Mononuclear Phagocytes to Avoid Excessive Immunopathology and to Orchestrate Repair

Overshooting systemic immune activation holds the risk of death like in early sepsis [70]. Similarly, overshooting organ inflammation holds the risk of acute organ dysfunction like in stroke, myocardial infarction, acute kidney injury, or severe pneumonia. As a consequence, numerous anti-inflammatory mediators provide a balance to immunostimulatory factors, a process that also allows the resolution of inflammation upon pathogen clearance [71–73]. Resolution of inflammation is initiated by a shift in the tissue microenvironment. For example, the early neutrophil influx into a PAMP-rich environment and DAMP release from necrotic cells can change once pathogen control is achieved, so that tissue environments display less PAMPs and DAMPs but become dominated by increasing numbers of apoptotic neutrophils. Macrophage clearance of apoptotic cells is already an important element of peripheral tolerance during homeostasis in healthy tissues, but it becomes an element of the resolution of inflammation in disease [71, 72]. Neutrophil phagocytosis triggers macrophage deactivation and the expression of anti-inflammatory mediators and growth factors that have the potential to stimulate tissue healing [74, 75]. In fact, apoptosis of activated neutrophils and T cells is a mechanism that prevents inappropriate or persistent immunopathology [74]. This also applies to the postinflammatory phase of sterile injuries (Figure 3). For example, transient ischemia reperfusion is associated with cell necrosis and DAMP release followed by the influx of neutrophils and classically activated macrophages for 1–3 days [40]. The excessive phagocytosis of apoptotic neutrophils activates the monocytic phagocytes to release TGF-β and IL-10 [76]. Serum amyloid-P, also named pentraxin-2, opsonizes apoptotic cells which further promotes the anti-inflammatory macrophage phenotype [77]. Infiltrating regulatory T cells also produce IL-10 and TGF-β, which further supports the polarization towards anti-inflammatory macrophages and also suppresses of T effector cells [78]. This deactivation of proinflammatory macrophages involves the transcription factor IRF4, which competes with IRF5, a nonredundant element of TLR and IL-1R signaling [79–82]. IRF4-deficiency does not allow this phenotype switch [80], hence, persistently activated macrophages contribute to ongoing immunopathology [83]. As another mechanism that promotes resolution of tissue injury, tissue dendritic cells produce pentraxin-3, which then blocks P selectin on the luminal surface of vascular endothelial cells, which blocks further immune cell recruitment [84–86].

The current macrophage classifications are derived from decent in vitro study conditions that have not yet integrated apoptotic cells as a stimulus of differentiation [31, 87–92]. However, the M2c phenotype of macrophages stimulated with IL-10 and TGF-β display certain characteristics of anti-inflammatory tissue macrophages (Figure 3) [31, 87–92]. The fact that M2c macrophages themselves produce large amounts of IL-10 illustrates how macrophages can amplify their surrounding environments by secreting similar cytokines in a feed-forward loop [93]. These cells are needed to enforce the resolution of inflammation, which is required to tip the balance of host defense and repair towards tissue regeneration (Figure 4). To enhance the regeneration process, anti-inflammatory macrophages acquire a phenotype of growth factor-producing cells that now actively drive epithelial or parenchymal repair. For example, macrophage depletion during the postinflammatory phase of sterile wounds delays wound healing and supports hemorrhage because of a persistent apoptosis of endothelial cells and detachment of the neuroepithelium [43, 94]. In addition, postischemic acute kidney injury involves the phenotypic switch from proinflammatory towards anti-inflammatory macrophages, a process driven by factors released by dying tubular epithelial cells and by the phagocytosis of apoptotic neutrophils [57, 95]. IRF4 or IRAK-M deficiency prevents this phenotype switch, which supports ongoing disease activity in a number of acute and chronic disease states [80, 83, 96–98]. In addition, treatment with recombinant IL-4/IL-10 or genetically modified or transfused IL-10-stimulated macrophages helps to resolve renal inflammation [87–90, 99]. The same phenomenon improves cardiac remodeling after myocardial infarction [100]. Glucocorticoids suppress tissue inflammation by inducing the anti-inflammatory phenotype of tissue macrophages [101, 102]. Monocyte recruitment to skeletal muscle may initially result in a proinflammatory macrophages phenotype, which then rapidly change their phenotype into anti-inflammatory macrophages that assist myogenesis and macrophage depletion that leads to a significantly reduced diameter of regenerating muscle fibers [103]. Toxic liver disease is another example of sterile organ dysfunction. CCl4 induces hepatocyte apoptosis and subsequent phagocytic clearance by Kupffer cells, a mechanism that suppresses liver inflammation [104]. Ischemia-reperfusion injury of the liver is associated with significant IL-10 expression, which was found to be crucial for the anti-inflammatory capacity of Kupffer cells [105]. In experimental schistosomiasis, IL-4Rα-deficiency of macrophages was sufficient to cause a lethal septic phenotype [106], which demonstrates the role of anti-inflammatory cytokines produced by alternatively activated macrophages in the gut and the liver, respectively [107]. Finally, axonal regeneration after spinal cord injury depends on the recruitment of IL-10-producing macrophages to the CNS [108].

The anti-inflammatory macrophage phenotype does not only contribute to the resolution of inflammation and the healing phase upon tissue injuries. Also non-necrotic environments of solid tumors induce alternative macrophage activation which then enforces tumor growth [109]. The same applies to degenerative tissue lesions or tissue damage upon slowly accumulating toxins dominated by apoptotic cell death [75].

5. Tissues Need Mononuclear Phagocytes for Effective Scaring When Epithelial or Parenchymal Healing Remains Incomplete

Evolution has maintained tissue scaring for its benefits for the function and survival of organisms. Scaring is necessary in more complex multicellular organisms when traumatic amputation or otherwise significant loss of tissue cannot be rapidly regenerated, a process that requires sealing and mechanical stabilization to assure function and survival. For example, a limited pericyte proliferation can assist vascular stability during regeneration upon injury [110]. However, myofibroblast proliferation and extensive fibrosis offer structural benefits only upon focal wounding and strongly depend on the site or compartment of injury. In diffuse fibrosis of the skin, like in progressive scleroderma, holds the potential to destroy the organ, a functional consequence that applies especially to organs that are commonly affected by diffuse injuries such as the lung, the liver, and the kidney [18, 111, 112]. But instead of taking fibrogenesis as a mechanism of progressive organ, destruction fibrous tissue mainly replaces lost parenchyma; therefore, inhibiting fibrogenesis may not necessarily be able to restore tissue function unless being accompanied by significant regeneration of the parenchyma. Therefore, apart from the healing of tendons, bones, and fasciae, only insufficient healing of epithelial and vascular structures is commonly associated with mesenchymal healing, that is, fibrosis when (1) the damage goes beyond epithelial layer injury, which can occur in some organs like skin, intestinal tract, pancreas and other glands or kidney. Damage to mesenchymal cell structures is more complex and requires more time, for example, in bone, tendons, heart, and skeletal muscle. (2) Local progenitor cells do not survive the injury phase. If at all terminally differentiated cells can divide is questionable and the concept of their dedifferentiation for mitotic repair remains under debate [113–120]. The evolving concept that terminally differentiated cells mostly regenerate from the division of committed local progenitor cells in all organs is appealing and could explain why regeneration remains insufficient when these cells get lost during a severe injury phase or undergo senescence, for example, during aging. (3) Repair is compromised by ongoing PAMP or DAMP exposure like during local infection or by persistent or remitting injuries that impair the repair process by persistent inflammation (Figure 4) [103].

An insufficient repair creates a microenvironment that becomes dominated by the persistent expression of multiple profibrotic cytokines [44, 94, 121]. In such environments, mononuclear phagocytes become a major source of profibrotic cytokines [3]. In vitro, IL-4 and IL-13 induce STAT6 signaling, which induces a macrophage phenotype that predominately releases fibronectin and other ECM molecules and that expresses mannose and scavenger receptors, IL-1R11, FIZZ, and YM-1, that is, M2a macrophages [31]. It remains to be determined whether anti-inflammatory and profibrotic macrophages clearly represent two different types of cells also in vivo, because macrophage plasticity usually creates a mixture or continuous variant shifts during tissue remodeling (Figure 4) [35]. However, a pro-fibrogenic phenotype of myeloid cells already exists at the level of circulating monocytes, that is, the fibrocyte that shares phenotypic similarities with monocytes and fibroblasts and that can produce large amounts of collagen [122–126], for example, in the liver [127], the lung [128], the heart [129], and in the kidney [60, 125] (Figure 3). However, their quantitative contribution to tissue scaring has been questioned by GFP lineage tracing of collagen 1α1-producing cells, that found only a minor contribution of fibrocytes to renal fibrogenesis and scaring [112, 130, 131].

Chemokine receptor CCR1 seems to be essential for profibrotic macrophage- and fibrocyte-mediated fibrosis because lack of CCR1 or CCR1 antagonism prevents progressive tissue scaring in many different organs and various types of injuries [12, 132–144]. Macrophages that contribute to dermal fibrosis express CXCR3 [145]. Insufficient macrophage activation in chronic diabetic leg ulcers delays scar formation, which can be restored by administering GM-CSF [146]. Similar mechanisms apply to progressive fibrosis of solid organs (Figure 3). Targeting the MCP-1/CCR2 axis [147, 148] or deficiency in CCR1/CCR5 blocked the recruitment of profibrotic macrophages, which was associated with less liver fibrosis [140] and renal fibrosis [132, 134, 137, 138, 149–151]. In the lung, CCR2 deficiency attenuated bleomycin-induced scaring [152], which was shown to be mediated by IL-13 signaling via IL-13-Rα1 and IL-13-Rα2 to stimulate TGFβ secretion in macrophages [153]. Together, tissues use their resident and infiltrating mononuclear phagocytes to fill the gaps of lost parenchyma, which stabilizes the tissue integrity. This is helpful upon focal injuries but may contribute to tissue loss in diffuse injuries, thus this evolutionally conserved danger control program often becomes a maladaptive disease process, especially when epithelial healing remains insufficient.

6. Tissues Need Fibrolytic Mononuclear Phagocytes to Clear Excess Extracellular Matrix

Progressive lung fibrosis, renal interstitial fibrosis, or liver cirrhosis is characterized by parenchymal cell loss which gets partially replaced by fibrous tissue. Whether fibrogenesis itself contributes to the loss of parenchymal cells remains under debate [112, 154]. However, it is a matter of fact that even though fibrosis is often associated with advanced disease, it does not always progress to end-stage organ failure [155]. In fact, fibrosis can be a transient process that stabilizes tissue integrity during repair and almost entirely resolves later [44]. For example, dermal wound healing ends in the smallest possible scar, after a skin cut. Evidence for inducible fibrolysis in the skin comes from recombinant TGFβ-3 application in humans as well as preclinical models [156]. TGFβ-3 application prevented excessive proliferation of myofibroblasts and scar formation similar to fetal wound healing [156].

Macrophages are capable of clearing ECM via the secretion of selected MMPs, a process that limits and potentially reverses fibrosis [156]. For example, scar-associated macrophages remove fibrous tissue that accumulates after toxic liver injury by secretion of MMP13 and by recruiting neutrophils to the scar tissue [157–159]. In addition, such “fibrolytic” macrophages secrete CXCL10, which blocks the proliferation of fibroblasts in bleomycin-induced pulmonary fibrosis [160]. Excessive scaring, obviously, increases the physiological capacity of tissue macrophages to break down ECM during homeostasis into a scar tissue-reducing phenotype. Hence fibrolytic macrophages need to be added to the list of functionally important macrophage phenotypes (Figures 2 and 3). Surface markers that clearly identify fibrolytic macrophages remain to be described. One should keep in mind that MMP-secreting macrophages have been reported to contribute to tissue degradation by chopping up basement membranes [160]. Therefore, the fibrolytic macrophage may also rather contribute to tissue atrophy and further reduce the size and function of a shrunken organ, if its presence is not associated with extensive regeneration of de novo parenchyma. In fibrotic livers, however, transfer of bone marrow-derived macrophages was shown to reverse hepatic fibrosis and to improve regeneration and function of the liver [160].

7. Summary and Conclusions

Most tissues host mononuclear phagocytes because they help them to maintain peripheral tolerance. Mononuclear phagocytes provide this support by processing “self” into tolerogenic signals to the immune system (all organs), by removing cell debris (e.g., bone marrow) and incoming pathogen components (e.g., liver), and by turning PAMP recognition into epithelial growth to maintain barriers (e.g., gut). As different tissues have different needs to maintain tolerance, mononuclear phagocytes display very heterogeneous phenotypes already during homeostasis. These phenotypes are a result of the specific environment, which is provided in each organ. Similarly, when tissue injuries alter the organ-specific tissue environment, also the resident as well as the infiltrating myeloid cells will be affected as a result of their plasticity to polarize to different phenotypes in different environments. PAMP- and DAMP-rich (necrotic) environments [161–204] prime proinflammatory monocytic phagocytes for host defense, which, however, involves immunopathology, especially during sterile inflammation. Postinflammatory environments including tumor stroma are dominated by apoptotic cell bodies, which trigger polarization towards anti-inflammatory or tumor-associated macrophages that suppress immunity and support cell growth, which could mean epithelial healing but also tumor growth. A healing tissue environment, especially during insufficient epithelial healing, is dominated by growth factors that prime macrophages towards a profibrotic phenotype secreting profibrotic cytokines and ECM components. Scar tissue is hypoxic and lacks growth factors, which enable fibrolytic macrophages to predominantly secrete proteases that remove ECM. Together, mononuclear phagocytes are amplifiers of their surrounding environments because the tissue primes macrophages according to its needs to stabilize and to reenforce the current environment. Thus, organ- and disease-phase-specific environments determine the associated macrophage and dendritic cell heterogeneity, which assures their support to maintain and regain tissue homeostasis in whatever condition. Pathogenic roles of these cells in diffuse tissue injuries are related to maladaptive wound healing programs.

Acknowledgments

M. Lech, M. Weidenbusch, and H. J. Anders were supported by Grants from the Deutsche Forschungsgemeinschaft (LE2621/2-1, AN372/11-1, and GRK1202). R. Gröbmair was supported by the Medical Faculty, University of Munich (FöFoLe program).

References

  1. F. Geissmann, M. G. Manz, S. Jung, M. H. Sieweke, M. Merad, and K. Ley, “Development of monocytes, macrophages, and dendritic cells,” Science, vol. 327, no. 5966, pp. 656–661, 2010. View at: Publisher Site | Google Scholar
  2. R. Medzhitov, “Origin and physiological roles of inflammation,” Nature, vol. 454, no. 7203, pp. 428–435, 2008. View at: Publisher Site | Google Scholar
  3. S. D. Ricardo, H. van Goor, and A. A. Eddy, “Macrophage diversity in renal injury and repair,” The Journal of Clinical Investigation, vol. 118, no. 11, pp. 3522–3530, 2008. View at: Publisher Site | Google Scholar
  4. P. Matzinger, “Friendly and dangerous signals: is the tissue in control?” Nature Immunology, vol. 8, no. 1, pp. 11–13, 2007. View at: Publisher Site | Google Scholar
  5. P. Matzinger and T. Kamala, “Tissue-based class control: the other side of tolerance,” Nature Reviews Immunology, vol. 11, no. 3, pp. 221–230, 2011. View at: Publisher Site | Google Scholar
  6. R. van Furth and Z. A. Cohn, “The origin and kinetics of mononuclear phagocytes,” Journal of Experimental Medicine, vol. 128, no. 3, pp. 415–435, 1968. View at: Google Scholar
  7. P. J. Nelson, A. J. Rees, M. D. Griffin, J. Hughes, C. Kurts, and J. Duffield, “The renal mononuclear phagocytic system,” Journal of the American Society of Nephrology, vol. 23, no. 2, pp. 194–203, 2012. View at: Google Scholar
  8. H. Yoshida, K. Kawane, M. Koike, Y. Mori, Y. Uchiyama, and S. Nagata, “Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells,” Nature, vol. 437, no. 7059, pp. 754–758, 2005. View at: Publisher Site | Google Scholar
  9. R. M. Steinman and Z. A. Cohn, “Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution,” The Journal of Experimental Medicine, vol. 137, pp. 1142–1162, 1973. View at: Google Scholar
  10. S. Gordon and P. R. Taylor, “Monocyte and macrophage heterogeneity,” Nature Reviews Immunology, vol. 5, no. 12, pp. 953–964, 2005. View at: Publisher Site | Google Scholar
  11. A. Ehninger and A. Trumpp, “The bone marrow stem cell niche grows up: mesenchymal stem cells and macrophages move in,” Journal of Experimental Medicine, vol. 208, no. 3, pp. 421–428, 2011. View at: Publisher Site | Google Scholar
  12. Z. Yang, B. Kong, D. M. Mosser, and X. Zhang, “TLRs, macrophages, and NK cells: our understandings of their functions in uterus and ovary,” International Immunopharmacology, vol. 11, pp. 1442–1450, 2011. View at: Publisher Site | Google Scholar
  13. R. John and P. J. Nelson, “Dendritic cells in the kidney,” Journal of the American Society of Nephrology, vol. 18, no. 10, pp. 2628–2635, 2007. View at: Publisher Site | Google Scholar
  14. J. M. Welzen-Coppens, C. G. van Helden-Meeuwsen, H. A. Drexhage, and M. A. Versnel, “Abnormalities of dendritic cell precursors in the pancreas of the nod mouse model of diabetes,” European Journal of Immunology, vol. 42, no. 1, pp. 186–194, 2012. View at: Google Scholar
  15. P. Sathe and K. Shortman, “The steady-state development of splenic dendritic cells,” Mucosal Immunology, vol. 1, no. 6, pp. 425–431, 2008. View at: Publisher Site | Google Scholar
  16. I. N. Crispe, “Liver antigen-presenting cells,” Journal of Hepatology, vol. 54, no. 2, pp. 357–365, 2011. View at: Publisher Site | Google Scholar
  17. A. M. Mowat and C. C. Bain, “Mucosal macrophages in intestinal homeostasis and inflammation,” Journal of Innate Immunity, vol. 3, pp. 550–564, 2011. View at: Google Scholar
  18. H. J. Anders, “Four danger response programs determine glomerular and tubulointerstitial kidney pathology: clotting, inflammation, epithelial and mesenchymal healing,” Organogenesis, vol. 8, pp. 29–40, 2012. View at: Google Scholar
  19. K. L. Rock, E. Latz, F. Ontiveros, and H. Kono, “The sterile inflammatory response,” Annual Review of Immunology, vol. 28, pp. 321–342, 2010. View at: Publisher Site | Google Scholar
  20. O. Takeuchi and S. Akira, “Pattern recognition receptors and inflammation,” Cell, vol. 140, no. 6, pp. 805–820, 2010. View at: Publisher Site | Google Scholar
  21. H. J. Anders, “Innate pathogen recognition in the kidney: toll-like receptors, NOD-like receptors, and RIG-like helicases,” Kidney International, vol. 72, no. 9, pp. 1051–1056, 2007. View at: Publisher Site | Google Scholar
  22. R. Allam, C. R. Scherbaum, M. N. Darisipudi et al., “Histones from dying renal cells aggravate kidney injury via tlr2 and tlr4,” Journal of the American Society of Nephrology, vol. 23, pp. 1375–1388, 2012. View at: Google Scholar
  23. P. Scaffidi, T. Misteli, and M. E. Bianchi, “Release of chromatin protein HMGB1 by necrotic cells triggers inflammation,” Nature, vol. 418, pp. 191–195, 2002. View at: Publisher Site | Google Scholar
  24. K. Wilhelm, J. Ganesan, T. Müller et al., “Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R,” Nature Medicine, vol. 16, no. 12, pp. 1434–1438, 2010. View at: Publisher Site | Google Scholar
  25. H. Kono, C. J. Chen, F. Ontiveros, and K. L. Rock, “Uric acid promotes an acute inflammatory response to sterile cell death in mice,” The Journal of Clinical Investigation, vol. 120, no. 6, pp. 1939–1949, 2010. View at: Publisher Site | Google Scholar
  26. L. Sorokin, “The impact of the extracellular matrix on inflammation,” Nature Reviews Immunology, vol. 10, no. 10, pp. 712–723, 2010. View at: Publisher Site | Google Scholar
  27. M. D. Säemann, T. Weichhart, M. Zeyda et al., “Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism,” The Journal of Clinical Investigation, vol. 115, no. 2, pp. 468–475, 2005. View at: Publisher Site | Google Scholar
  28. M. N. Darisipudi, D. Thomasova, S. R. Mulay et al., “Uromodulin trigegrs il-1ß-dependent innate immunity via the nlrp3 inflammasome,” Journal of the American Society of Nephrology, vol. 23, no. 11, pp. 1783–1789, 2012. View at: Google Scholar
  29. T. Kawai and S. Akira, “Toll-like receptors and their crosstalk with other innate receptors in infection and immunity,” Immunity, vol. 34, no. 5, pp. 637–650, 2011. View at: Publisher Site | Google Scholar
  30. P. S. Patole, S. Schubert, K. Hildinger et al., “Toll-like receptor-4: renal cells and bone marrow cells signal for neutrophil recruitment during pyelonephritis,” Kidney International, vol. 68, no. 6, pp. 2582–2587, 2005. View at: Publisher Site | Google Scholar
  31. A. Mantovani, A. Sica, S. Sozzani, P. Allavena, A. Vecchi, and M. Locati, “The chemokine system in diverse forms of macrophage activation and polarization,” Trends in Immunology, vol. 25, no. 12, pp. 677–686, 2004. View at: Publisher Site | Google Scholar
  32. M. Lech, A. Avila-Ferrufino, V. Skuginna, H. E. Susanti, and H. J. Anders, “Quantitative expression of RIG-like helicase, NOD-like receptor and inflammasome-related mRNAs in humans and mice,” International Immunology, vol. 22, no. 9, pp. 717–728, 2010. View at: Publisher Site | Google Scholar
  33. M. Lech, H. E. Susanti, C. Rommele, R. Grobmayr, R. Gunthner, and H. J. Anders, “Quantitative expression of c-type lectin receptors in humans and mice,” International Journal of Molecular Sciences, vol. 13, pp. 10113–10131, 2012. View at: Google Scholar
  34. T. Krausgruber, K. Blazek, T. Smallie et al., “IRF5 promotes inflammatory macrophage polarization and T H1-TH17 responses,” Nature Immunology, vol. 12, no. 3, pp. 231–238, 2011. View at: Publisher Site | Google Scholar
  35. 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, pp. 1035–1044, 2011. View at: Google Scholar
  36. H. J. Anders, “Toll-like receptors and danger signaling in kidney injury,” Journal of the American Society of Nephrology, vol. 21, no. 8, pp. 1270–1274, 2010. View at: Publisher Site | Google Scholar
  37. M. Benoit, B. Desnues, and J. L. Mege, “Macrophage polarization in bacterial infections,” Journal of Immunology, vol. 181, no. 6, pp. 3733–3739, 2008. View at: Google Scholar
  38. H. Kono and K. L. Rock, “How dying cells alert the immune system to danger,” Nature Reviews Immunology, vol. 8, no. 4, pp. 279–289, 2008. View at: Publisher Site | Google Scholar
  39. K. L. Rock, J. J. Lai, and H. Kono, “Innate and adaptive immune responses to cell death,” Immunological Reviews, vol. 243, pp. 191–205, 2011. View at: Google Scholar
  40. S. Swaminathan and M. D. Griffin, “First responders: understanding monocyte-lineage traffic in the acutely injured kidney,” Kidney International, vol. 74, no. 12, pp. 1509–1511, 2008. View at: Publisher Site | Google Scholar
  41. A. S. Tarnawski and A. Ahluwalia, “Molecular mechanisms of epithelial regeneration and neovascularization during healing of gastric and esophageal ulcers,” Current Medicinal Chemistry, vol. 19, pp. 16–27, 2012. View at: Google Scholar
  42. A. J. Cowin, M. P. Brosnan, T. M. Holmes, and M. W. Ferguson, “Endogenous inflammatory response to dermal wound healing in the fetal and adult mouse,” Developmental Dynamics, vol. 212, pp. 385–393, 1998. View at: Google Scholar
  43. T. Lucas, A. Waisman, R. Ranjan et al., “Differential roles of macrophages in diverse phases of skin repair,” Journal of Immunology, vol. 184, no. 7, pp. 3964–3977, 2010. View at: Publisher Site | Google Scholar
  44. G. C. Gurtner, S. Werner, Y. Barrandon, and M. T. Longaker, “Wound repair and regeneration,” Nature, vol. 453, no. 7193, pp. 314–321, 2008. View at: Publisher Site | Google Scholar
  45. A. Sindrilaru, T. Peters, S. Wieschalka et al., “An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice,” The Journal of Clinical Investigation, vol. 121, no. 3, pp. 985–997, 2011. View at: Publisher Site | Google Scholar
  46. S. Recalcati, M. Locati, E. Gammella, P. Invernizzi, and G. Cairo, “Iron levels in polarized macrophages: regulation of immunity and autoimmunity,” Autoimmunity Reviews, vol. 11, no. 12, pp. 883–889, 2012. View at: Google Scholar
  47. Y. Ikezumi, R. C. Atkins, and D. J. Nikolic-Paterson, “Interferon-γ augments acute macrophage-mediated renal injury via a glucocorticoid-sensitive mechanism,” Journal of the American Society of Nephrology, vol. 14, no. 4, pp. 888–898, 2003. View at: Publisher Site | Google Scholar
  48. H. J. Anders, V. Vielhauer, V. Eis et al., “Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice,” The FASEB Journal, vol. 18, no. 3, pp. 534–536, 2004. View at: Google Scholar
  49. R. Allam, R. D. Pawar, O. P. Kulkarni et al., “Viral 5′-triphosphate RNA and non-CpG DNA aggravate autoimmunity and lupus nephritis via distinctTLR-independent immune responses,” European Journal of Immunology, vol. 38, no. 12, pp. 3487–3498, 2008. View at: Publisher Site | Google Scholar
  50. P. S. Patole, H. J. Gröne, S. Segerer et al., “Viral double-stranded RNA aggravates lupus nephritis through toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells,” Journal of the American Society of Nephrology, vol. 16, no. 5, pp. 1326–1338, 2005. View at: Publisher Site | Google Scholar
  51. P. S. Patole, R. D. Pawar, J. Lichtnekert et al., “Coactivation of toll-like receptor-3 and -7 in immune complex glomerulonephritis,” Journal of Autoimmunity, vol. 29, no. 1, pp. 52–59, 2007. View at: Publisher Site | Google Scholar
  52. R. D. Pawar, P. S. Patole, A. Ellwart et al., “Ligands to nucleic acid-specific toll-like receptors and the onset of lupus nephritis,” Journal of the American Society of Nephrology, vol. 17, no. 12, pp. 3365–3373, 2006. View at: Publisher Site | Google Scholar
  53. R. D. Pawar, P. S. Patole, D. Zecher et al., “Toll-like receptor-7 modulates immune complex glomerulonephritis,” Journal of the American Society of Nephrology, vol. 17, no. 1, pp. 141–149, 2006. View at: Publisher Site | Google Scholar
  54. H. J. Anders, B. Banas, Y. Linde et al., “Bacterial CpG-DNA aggravates immune complex glomerulonephritis: role of TLR9-mediated expression of chemokines and chemokine receptors,” Journal of the American Society of Nephrology, vol. 14, no. 2, pp. 317–326, 2003. View at: Publisher Site | Google Scholar
  55. M. D. Jose, Y. Ikezumi, N. van Rooijen, R. C. Atkins, and S. J. Chadban, “Macrophages act as effectors of tissue damage in acute renal allograft rejection,” Transplantation, vol. 76, no. 7, pp. 1015–1022, 2003. View at: Publisher Site | Google Scholar
  56. J. V. Bonventre and A. Zuk, “Ischemic acute renal failure: an inflammatory disease?” Kidney International, vol. 66, no. 2, pp. 480–485, 2004. View at: Publisher Site | Google Scholar
  57. S. Lee, S. Huen, H. Nishio et al., “Distinct macrophage phenotypes contribute to kidney injury and repair,” Journal of the American Society of Nephrology, vol. 22, no. 2, pp. 317–326, 2011. View at: Publisher Site | Google Scholar
  58. M. Lech, A. Avila-Ferrufino, R. Allam et al., “Resident dendritic cells prevent postischemic acute renal failure by help of single Ig IL-1 receptor-related protein,” Journal of Immunology, vol. 183, no. 6, pp. 4109–4118, 2009. View at: Publisher Site | Google Scholar
  59. Y. Wang, Y. Wang, Q. Cai et al., “By homing to the kidney, activated macrophages potently exacerbate renal injury,” American Journal of Pathology, vol. 172, no. 6, pp. 1491–1499, 2008. View at: Publisher Site | Google Scholar
  60. H. J. Anders and M. Ryu, “Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis,” Kidney International, vol. 80, pp. 915–925, 2011. View at: Publisher Site | Google Scholar
  61. O. Kulkarni, D. Eulberg, N. Selve et al., “Anti-Ccl2 Spiegelmer permits 75% dose reduction of cyclophosphamide to control diffuse proliferative lupus nephritis and pneumonitis in MRL-Fas(lpr) mice,” Journal of Pharmacology and Experimental Therapeutics, vol. 328, no. 2, pp. 371–377, 2009. View at: Publisher Site | Google Scholar
  62. O. Kulkarni, R. D. Pawar, W. Purschke et al., “Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice,” Journal of the American Society of Nephrology, vol. 18, no. 8, pp. 2350–2358, 2007. View at: Publisher Site | Google Scholar
  63. I. L. King, T. L. Dickendesher, and B. M. Segal, “Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease,” Blood, vol. 113, no. 14, pp. 3190–3197, 2009. View at: Publisher Site | Google Scholar
  64. A. Mildner, M. MacK, H. Schmidt et al., “CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system,” Brain, vol. 132, no. 9, pp. 2487–2500, 2009. View at: Publisher Site | Google Scholar
  65. A. V. Chervonsky, “Influence of microbial environment on autoimmunity,” Nature Immunology, vol. 11, no. 1, pp. 28–35, 2010. View at: Publisher Site | Google Scholar
  66. R. Allam and H. J. Anders, “The role of innate immunity in autoimmune tissue injury,” Current Opinion in Rheumatology, vol. 20, no. 5, pp. 538–544, 2008. View at: Publisher Site | Google Scholar
  67. M. Ryu, O. P. Kulkarni, E. Radomska, N. Miosge, O. Gross, and H. J. Anders, “Bacterial CpG-DNA accelerates Alport glomerulosclerosis by inducing an M1 macrophage phenotype and tumor necrosis factor-α-mediated podocyte loss,” Kidney International, vol. 79, no. 2, pp. 189–198, 2011. View at: Publisher Site | Google Scholar
  68. H. J. Anders, D. Zecher, R. D. Pawar, and P. S. Patole, “Molecular mechanisms of autoimmunity triggered by microbial infection,” Arthritis Research and Therapy, vol. 7, no. 5, pp. 215–224, 2005. View at: Publisher Site | Google Scholar
  69. R. D. Pawar, L. Castrezana-Lopez, R. Allam et al., “Bacterial lipopeptide triggers massive albuminuria in murine lupus nephritis by activating toll-like receptor 2 at the glomerular filtration barrier,” Immunology, vol. 128, no. 1, pp. e206–e221, 2009. View at: Publisher Site | Google Scholar
  70. D. J. Stearns-Kurosawa, M. F. Osuchowski, C. Valentine, S. Kurosawa, and D. G. Remick, “The pathogenesis of sepsis,” Annual Review of Pathology, vol. 6, pp. 19–48, 2011. View at: Publisher Site | Google Scholar
  71. J. Han and R. J. Ulevitch, “Limiting inflammatory responses during activation of innate immunity,” Nature Immunology, vol. 6, no. 12, pp. 1198–1205, 2005. View at: Publisher Site | Google Scholar
  72. C. N. Serhan and J. Savill, “Resolution of inflammation: the beginning programs the end,” Nature Immunology, vol. 6, no. 12, pp. 1191–1197, 2005. View at: Publisher Site | Google Scholar
  73. H. J. Anders, V. Vielhauer, and D. Schlöndorff, “Chemokines and chemokine receptors are involved in the resolution or progression of renal disease,” Kidney International, vol. 63, no. 2, pp. 401–415, 2003. View at: Publisher Site | Google Scholar
  74. J. Savill, “Apoptosis in resolution of inflammation,” Journal of Leukocyte Biology, vol. 61, no. 4, pp. 375–380, 1997. View at: Google Scholar
  75. J. Savill, C. Gregory, and C. Haslett, “Eat me or die,” Science, vol. 302, no. 5650, pp. 1516–1517, 2003. View at: Publisher Site | Google Scholar
  76. M. Lucas, L. M. Stuart, J. Savill, and A. Lacy-Hulbert, “Apoptotic cells and innate immune stimuli combine to regulate macrophage cytokine secretion,” Journal of Immunology, vol. 171, no. 5, pp. 2610–2615, 2003. View at: Google Scholar
  77. J. S. Duffield, “Macrophages and immunologic inflammation of the kidney,” Seminars in Nephrology, vol. 30, no. 3, pp. 234–254, 2010. View at: Publisher Site | Google Scholar
  78. G. Liu, H. Ma, L. Qiu et al., “Phenotypic and functional switch of macrophages induced by regulatory CD4 CD25 T cells in mice,” Immunology and Cell Biology, vol. 89, no. 1, pp. 130–142, 2011. View at: Publisher Site | Google Scholar
  79. H. Negishi, Y. Ohba, H. Yanai et al., “Negative regulation of Toll-like-receptor signaling by IRF-4,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 44, pp. 15989–15994, 2005. View at: Publisher Site | Google Scholar
  80. T. Satoh, O. Takeuchi, A. Vandenbon et al., “The jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection,” Nature Immunology, vol. 11, no. 10, pp. 936–944, 2010. View at: Publisher Site | Google Scholar
  81. C. El Chartouni, L. Schwarzfischer, and M. Rehli, “Interleukin-4 induced interferon regulatory factor (Irf) 4 participates in the regulation of alternative macrophage priming,” Immunobiology, vol. 215, no. 9-10, pp. 821–825, 2010. View at: Publisher Site | Google Scholar
  82. M. Ishii, H. Wen, C. A. S. Corsa et al., “Epigenetic regulation of the alternatively activated macrophage phenotype,” Blood, vol. 114, no. 15, pp. 3244–3254, 2009. View at: Publisher Site | Google Scholar
  83. S. Lassen, M. Lech, C. Römmele, H. W. Mittruecker, T. W. Mak, and H. J. Anders, “Ischemia reperfusion induces IFN regulatory factor 4 in renal dendritic cells, which suppresses postischemic inflammation and prevents acute renal failure,” Journal of Immunology, vol. 185, no. 3, pp. 1976–1983, 2010. View at: Publisher Site | Google Scholar
  84. B. Bottazzi, A. Doni, C. Garlanda, and A. Mantovani, “An integrated view of humoral innate immunity: pentraxins as a paradigm,” Annual Review of Immunology, vol. 28, pp. 157–183, 2010. View at: Publisher Site | Google Scholar
  85. L. Deban, R. C. Russo, M. Sironi et al., “Regulation of leukocyte recruitment by the long pentraxin PTX3,” Nature Immunology, vol. 11, no. 4, pp. 328–334, 2010. View at: Publisher Site | Google Scholar
  86. M. Lech, C. Römmele, O. P. Kulkarni et al., “Lack of the long pentraxin PTX3 promotes autoimmune lung disease but not glomerulonephritis in murine systemic lupus erythematosus,” PLoS One, vol. 6, no. 5, Article ID e20118, 2011. View at: Publisher Site | Google Scholar
  87. Q. Cao, Y. Wang, D. Zheng et al., “IL-10/TGF-β-modified macrophages induce regulatory T cells and protect against adriamycin nephrosis,” Journal of the American Society of Nephrology, vol. 21, no. 6, pp. 933–942, 2010. View at: Publisher Site | Google Scholar
  88. D. C. Kluth, C. V. Ainslie, W. P. Pearce et al., “Macrophages transfected with adenovirus to express IL-4 reduce inflammation in experimental glomerulonephritis,” Journal of Immunology, vol. 166, no. 7, pp. 4728–4736, 2001. View at: Google Scholar
  89. Y. Wang, Y. P. Wang, G. Zheng et al., “Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease,” Kidney International, vol. 72, no. 3, pp. 290–299, 2007. View at: Publisher Site | Google Scholar
  90. D. Zheng, Y. Wang, Q. Cao et al., “Transfused macrophages ameliorate pancreatic and renal injury in murine diabetes mellitus,” Nephron, vol. 118, no. 4, pp. e87–e99, 2011. View at: Publisher Site | Google Scholar
  91. K. Barczyk, J. Ehrchen, K. Tenbrock et al., “Glucocorticoids promote survival of anti-inflammatory macrophages via stimulation of adenosine receptor A3,” Blood, vol. 116, no. 3, pp. 446–455, 2010. View at: Publisher Site | Google Scholar
  92. R. Bertalan, A. Patocs, B. Vasarhelyi et al., “Association between birth weight in preterm neonates and the BclI polymorphism of the glucocorticoid receptor gene,” Journal of Steroid Biochemistry and Molecular Biology, vol. 111, no. 1-2, pp. 91–94, 2008. View at: Publisher Site | Google Scholar
  93. D. M. Mosser and J. P. Edwards, “Exploring the full spectrum of macrophage activation,” Nature Reviews Immunology, vol. 8, no. 12, pp. 958–969, 2008. View at: Publisher Site | Google Scholar
  94. A. J. Singer and R. A. F. Clark, “Cutaneous wound healing,” The New England Journal of Medicine, vol. 341, no. 10, pp. 738–746, 1999. View at: Publisher Site | Google Scholar
  95. A. A. Filardy, D. R. Pires, M. P. Nunes et al., “Proinflammatory clearance of apoptotic neutrophils induces an IL-12 lowIL-10high regulatory phenotype in macrophages,” Journal of Immunology, vol. 185, no. 4, pp. 2044–2050, 2010. View at: Publisher Site | Google Scholar
  96. M. Noris, P. Cassis, N. Azzollini et al., “The toll-IL-1R member Tir8/SIGIRR negatively regulates adaptive immunity against kidney grafts,” Journal of Immunology, vol. 183, no. 7, pp. 4249–4260, 2009. View at: Publisher Site | Google Scholar
  97. M. Lech, C. Kantner, O. P. Kulkarni et al., “Interleukin-1 receptor-associated kinase-m suppresses systemic lupus erythematosus,” Annals of the Rheumatic Diseases, vol. 70, pp. 2207–2217, 2011. View at: Google Scholar
  98. M. Lech, M. Weidenbusch, O. P. Kulkarni et al., “IRF4 deficiency abrogates lupus nephritis despite enhancing systemic cytokine production,” Journal of the American Society of Nephrology, vol. 22, no. 8, pp. 1443–1452, 2011. View at: Publisher Site | Google Scholar
  99. X. R. Huang, A. R. Kitching, P. G. Tipping, and S. R. Holdsworth, “Interleukin-10 inhibits macrophage-induced glomerular injury,” Journal of the American Society of Nephrology, vol. 11, no. 2, pp. 262–269, 2000. View at: Google Scholar
  100. H. Morimoto, M. Takahashi, Y. Shiba et al., “Bone marrow-derived CXCR4+ cells mobilized by macrophage colony-stimulating factor participate in the reduction of infarct area and improvement of cardiac remodeling after myocardial infarction in mice,” American Journal of Pathology, vol. 171, no. 3, pp. 755–766, 2007. View at: Publisher Site | Google Scholar
  101. Y. Ikezumi, T. Suzuki, T. Karasawa et al., “Contrasting effects of steroids and mizoribine on macrophage activation and glomerular lesions in rat Thy-1 mesangial proliferative glomerulonephritis,” American Journal of Nephrology, vol. 31, no. 3, pp. 273–282, 2010. View at: Publisher Site | Google Scholar
  102. M. Ghielli, W. A. Verstrepen, E. J. Nouwen, and M. E. De Broe, “Inflammatory cells in renal regeneration,” Renal Failure, vol. 18, no. 3, pp. 355–375, 1996. View at: Google Scholar
  103. L. Arnold, A. Henry, F. Poron et al., “Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis,” Journal of Experimental Medicine, vol. 204, no. 5, pp. 1057–1069, 2007. View at: Publisher Site | Google Scholar
  104. J. Shi, K. Aisaki, Y. Ikawa, and K. Wake, “Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride,” American Journal of Pathology, vol. 153, no. 2, pp. 515–525, 1998. View at: Google Scholar
  105. F. Ren, Z. Duan, Q. Cheng et al., “Inhibition of glycogen synthase kinase 3 beta ameliorates liver ischemia reperfusion injury by way of an interleukin-10-mediated immune regulatory mechanism,” Hepatology, vol. 54, no. 2, pp. 687–696, 2011. View at: Publisher Site | Google Scholar
  106. D. R. Herbert, C. Hölscher, M. Mohrs et al., “Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology,” Immunity, vol. 20, no. 5, pp. 623–635, 2004. View at: Publisher Site | Google Scholar
  107. L. Barron and T. A. Wynn, “Macrophage activation governs schistosomiasis-induced inflammation and fibrosis,” European Journal of Immunology, vol. 41, pp. 2509–2514, 2011. View at: Google Scholar
  108. R. Shechter, A. London, C. Varol et al., “Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice,” PLoS Medicine, vol. 6, no. 7, Article ID e1000113, 2009. View at: Publisher Site | Google Scholar
  109. A. Mantovani, G. Germano, F. Marchesi, M. Locatelli, and S. K. Biswas, “Cancer-promoting tumor-associated macrophages: new vistas and open questions,” European Journal of Immunology, vol. 41, pp. 2522–2525, 2011. View at: Google Scholar
  110. C. Schrimpf, C. Xin, G. Campanholle et al., “Pericyte timp3 and adamts1 modulate vascular stability after kidney injury,” Journal of the American Society of Nephrology, vol. 23, pp. 868–883, 2012. View at: Google Scholar
  111. T. T. Lu, “Dendritic cells: novel players in fibrosis and scleroderma,” Current Rheumatology Reports, vol. 14, no. 1, pp. 30–38, 2012. View at: Google Scholar
  112. M. Zeisberg and E. G. Neilson, “Mechanisms of tubulointerstitial fibrosis,” Journal of the American Society of Nephrology, vol. 21, no. 11, pp. 1819–1834, 2010. View at: Publisher Site | Google Scholar
  113. J. S. Duffield and B. D. Humphreys, “Origin of new cells in the adult kidney: results from genetic labeling techniques,” Kidney International, vol. 79, no. 5, pp. 494–501, 2011. View at: Publisher Site | Google Scholar
  114. B. D. Humphreys, M. T. Valerius, A. Kobayashi et al., “Intrinsic epithelial cells repair the kidney after injury,” Cell Stem Cell, vol. 2, no. 3, pp. 284–291, 2008. View at: Publisher Site | Google Scholar
  115. B. D. Humphreys and J. V. Bonventre, “Mesenchymal stem cells in acute kidney injury,” Annual Review of Medicine, vol. 59, pp. 311–325, 2008. View at: Publisher Site | Google Scholar
  116. M. Langworthy, B. Zhou, M. de Caestecker, G. Moeckel, and H. S. Baldwin, “NFATc1 identifies a population of proximal tubule cell progenitors,” Journal of the American Society of Nephrology, vol. 20, no. 2, pp. 311–321, 2009. View at: Publisher Site | Google Scholar
  117. C. Blanpain, V. Horsley, and E. Fuchs, “Epithelial stem cells: turning over new leaves,” Cell, vol. 128, no. 3, pp. 445–458, 2007. View at: Publisher Site | Google Scholar
  118. P. Romagnani, “Toward the identification of a "renopoietic system"?” Stem Cells, vol. 27, no. 9, pp. 2247–2253, 2009. View at: Publisher Site | Google Scholar
  119. V. Coskun, H. Wu, B. Blanchi et al., “CD133+ neural stem cells in the ependyma of mammalian postnatal forebrain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 3, pp. 1026–1031, 2008. View at: Publisher Site | Google Scholar
  120. M. L. Angelotti, E. Ronconi, L. Ballerini et al., “Characterization of renal progenitors committed toward tubular lineage and their regenerative potential in renal tubular injury,” Stem Cells, vol. 30, pp. 1714–1725, 2012. View at: Google Scholar
  121. L. Yang, T. Y. Besschetnova, C. R. Brooks, J. V. Shah, and J. V. Bonventre, “Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury,” Nature Medicine, vol. 16, no. 5, pp. 535–543, 2010. View at: Publisher Site | Google Scholar
  122. T. E. Quan, S. E. Cowper, and R. Bucala, “The role of circulating fibrocytes in fibrosis,” Current Rheumatology Reports, vol. 8, no. 2, pp. 145–150, 2006. View at: Publisher Site | Google Scholar
  123. D. Pilling, T. Fan, D. Huang, B. Kaul, and R. H. Gomer, “Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts,” PLoS One, vol. 4, no. 10, Article ID e7475, 2009. View at: Publisher Site | Google Scholar
  124. M. Schmidt, G. Sun, M. A. Stacey, L. Mori, and S. Mattoli, “Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma,” Journal of Immunology, vol. 171, no. 1, pp. 380–389, 2003. View at: Google Scholar
  125. M. Niedermeier, B. Reich, M. R. Gomez et al., “CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 42, pp. 17892–17897, 2009. View at: Publisher Site | Google Scholar
  126. N. Sakai, K. Furuichi, Y. Shinozaki et al., “Fibrocytes are involved in the pathogenesis of human chronic kidney disease,” Human Pathology, vol. 41, no. 5, pp. 672–678, 2010. View at: Publisher Site | Google Scholar
  127. S. J. Forbes, F. P. Russo, V. Rey et al., “A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis,” Gastroenterology, vol. 126, no. 4, pp. 955–963, 2004. View at: Publisher Site | Google Scholar
  128. A. Andersson-Sjöland, C. G. de Alba, K. Nihlberg et al., “Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis,” International Journal of Biochemistry and Cell Biology, vol. 40, no. 10, pp. 2129–2140, 2008. View at: Publisher Site | Google Scholar
  129. M. J. van Amerongen, G. Bou-Gharios, E. R. Popa et al., “Bone marrow-derived myofibroblasts contribute functionally to scar formation after myocardial infarction,” Journal of Pathology, vol. 214, no. 3, pp. 377–386, 2008. View at: Publisher Site | Google Scholar
  130. I. Grgic, J. S. Duffield, and B. D. Humphreys, “The origin of interstitial myofibroblasts in chronic kidney disease,” Pediatric Nephrology, vol. 27, no. 2, pp. 183–193, 2012. View at: Publisher Site | Google Scholar
  131. S. L. Lin, T. Kisseleva, D. A. Brenner, and J. S. Duffield, “Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney,” American Journal of Pathology, vol. 173, no. 6, pp. 1617–1627, 2008. View at: Publisher Site | Google Scholar
  132. V. Vielhauer, H. J. Anders, M. Mack et al., “Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes,” Journal of the American Society of Nephrology, vol. 12, no. 6, pp. 1173–1187, 2001. View at: Google Scholar
  133. H. J. Anders, V. Vielhauer, M. Kretzler et al., “Chemokine and chemokine receptor expression during initiation and resolution of immune complex glomerulonephritis,” Journal of the American Society of Nephrology, vol. 12, no. 5, pp. 919–931, 2001. View at: Google Scholar
  134. H. J. Anders, V. Vielhauer, M. Frink et al., “A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation,” The Journal of Clinical Investigation, vol. 109, no. 2, pp. 251–259, 2002. View at: Publisher Site | Google Scholar
  135. J. Bedke, E. Kiss, L. Schaefer et al., “Beneficial effects of CCR1 blockade on the progression of chronic renal allograft damage,” American Journal of Transplantation, vol. 7, no. 3, pp. 527–537, 2007. View at: Publisher Site | Google Scholar
  136. K. Blease, B. Mehrad, T. J. Standiford et al., “Airway remodeling is absent in CCR1(-/-) mice during chronic fungal allergic airway disease,” Journal of Immunology, vol. 165, no. 3, pp. 1564–1572, 2000. View at: Google Scholar
  137. V. Eis, B. Luckow, V. Vielhauer et al., “Chemokine receptor ccr1 but not ccr5 mediates leukocyte recruitment and subsequent renal fibrosis after unilateral ureteral obstruction,” Journal of the American Society of Nephrology, vol. 15, no. 2, pp. 337–347, 2004. View at: Publisher Site | Google Scholar
  138. V. Ninichuk and H. J. Anders, “Chemokine receptor CCR1: a new target for progressive kidney disease,” American Journal of Nephrology, vol. 25, no. 4, pp. 365–372, 2005. View at: Publisher Site | Google Scholar
  139. D. Scholten, D. Reichart, Y. H. Paik et al., “Migration of fibrocytes in fibrogenic liver injury,” The American Journal of Pathology, vol. 179, pp. 189–198, 2011. View at: Google Scholar
  140. E. Seki, S. de Minicis, S. Inokuchi et al., “CCR2 promotes hepatic fibrosis in mice,” Hepatology, vol. 50, no. 1, pp. 185–197, 2009. View at: Publisher Site | Google Scholar
  141. A. Tokuda, M. Itakura, N. Onai, H. Kimura, T. Kuriyama, and K. Matsushima, “Pivotal role of CCR1-positive leukocytes in bleomycin-induced lung fibrosis in mice,” Journal of Immunology, vol. 164, no. 5, pp. 2745–2751, 2000. View at: Google Scholar
  142. V. Vielhauer, E. Berning, V. Eis et al., “CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome,” Kidney International, vol. 66, no. 6, pp. 2264–2278, 2004. View at: Publisher Site | Google Scholar
  143. H. J. Anders, E. Belemezova, V. Eis et al., “Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice,” Journal of the American Society of Nephrology, vol. 15, no. 6, pp. 1504–1513, 2004. View at: Publisher Site | Google Scholar
  144. V. Ninichuk, O. Gross, C. Reichel et al., “Delayed chemokine receptor 1 blockade prolongs survival in collagen 4A3-deficient mice with alport disease,” Journal of the American Society of Nephrology, vol. 16, no. 4, pp. 977–985, 2005. View at: Publisher Site | Google Scholar
  145. Y. Ishida, J. L. Gao, and P. M. Murphy, “Chemokine receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function,” Journal of Immunology, vol. 180, no. 1, pp. 569–579, 2008. View at: Google Scholar
  146. Y. Fang, J. Shen, M. Yao, K. W. Beagley, B. D. Hambly, and S. Bao, “Granulocyte-macrophage colony-stimulating factor enhances wound healing in diabetes via upregulation of proinflammatory cytokines,” British Journal of Dermatology, vol. 162, no. 3, pp. 478–486, 2010. View at: Publisher Site | Google Scholar
  147. M. Imamura, T. Ogawa, Y. Sasaguri, K. Chayama, and H. Ueno, “Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats,” Gastroenterology, vol. 128, no. 1, pp. 138–146, 2005. View at: Publisher Site | Google Scholar
  148. K. R. Karlmark, R. Weiskirchen, H. W. Zimmermann et al., “Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis,” Hepatology, vol. 50, no. 1, pp. 261–274, 2009. View at: Publisher Site | Google Scholar
  149. K. Kitagawa, T. Wada, K. Furuichi et al., “Blockade of CCR2 ameliorates progressive fibrosis in kidney,” American Journal of Pathology, vol. 165, no. 1, pp. 237–246, 2004. View at: Google Scholar
  150. T. Wada, K. Furuichi, N. Sakai et al., “Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis,” Journal of the American Society of Nephrology, vol. 15, no. 4, pp. 940–948, 2004. View at: Publisher Site | Google Scholar
  151. V. Ninichuk, S. Clauss, O. Kulkarni et al., “Late onset of Ccl2 blockade with the Spiegelmer mNOX-E36-3′PEG prevents glomerulosclerosis and improves glomerular filtration rate in db/db mice,” American Journal of Pathology, vol. 172, no. 3, pp. 628–637, 2008. View at: Publisher Site | Google Scholar
  152. T. Okuma, Y. Terasaki, K. Kaikita et al., “C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases,” Journal of Pathology, vol. 204, no. 5, pp. 594–604, 2004. View at: Publisher Site | Google Scholar
  153. S. Fichtner-Feigl, W. Strober, K. Kawakami, R. K. Puri, and A. Kitani, “IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis,” Nature Medicine, vol. 12, no. 1, pp. 99–106, 2006. View at: Publisher Site | Google Scholar
  154. V. Ninichuk, O. Gross, S. Segerer et al., “Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice,” Kidney International, vol. 70, no. 1, pp. 121–129, 2006. View at: Publisher Site | Google Scholar
  155. S. J. Leibovich and R. Ross, “The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum,” American Journal of Pathology, vol. 78, no. 1, pp. 71–100, 1975. View at: Google Scholar
  156. N. L. Occleston, S. O'Kane, H. G. Laverty et al., “Discovery and development of avotermin (recombinant human transforming growth factor beta 3): a new class of prophylactic therapeutic for the improvement of scarring,” Wound Repair and Regeneration, vol. 19, supplement 1, pp. S38–S48, 2011. View at: Publisher Site | Google Scholar
  157. J. S. Duffield, S. J. Forbes, C. M. Constandinou et al., “Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair,” The Journal of Clinical Investigation, vol. 115, no. 1, pp. 56–65, 2005. View at: Publisher Site | Google Scholar
  158. J. A. Fallowfield, M. Mizuno, T. J. Kendall et al., “Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis,” Journal of Immunology, vol. 178, no. 8, pp. 5288–5295, 2007. View at: Google Scholar
  159. M. W. Harty, E. F. Papa, H. M. Huddleston et al., “Hepatic macrophages promote the neutrophil-dependent resolution of fibrosis in repairing cholestatic rat livers,” Surgery, vol. 143, no. 5, pp. 667–678, 2008. View at: Publisher Site | Google Scholar
  160. D. Jiang, J. Liang, G. S. Campanella et al., “Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4,” The Journal of Clinical Investigation, vol. 120, no. 6, pp. 2049–2057, 2010. View at: Publisher Site | Google Scholar
  161. D. S. Tian, Q. Dong, D. J. Pan et al., “Attenuation of astrogliosis by suppressing of microglial proliferation with the cell cycle inhibitor olomoucine in rat spinal cord injury model,” Brain Research, vol. 1154, no. 1, pp. 206–214, 2007. View at: Publisher Site | Google Scholar
  162. C. C. Leonardo, A. K. Eakin, J. M. Ajmo et al., “Delayed administration of a matrix metalloproteinase inhibitor limits progressive brain injury after hypoxia-ischemia in the neonatal rat,” Journal of Neuroinflammation, vol. 5, article 34, 2008. View at: Publisher Site | Google Scholar
  163. G. Raivich, M. T. Moreno-Flores, J. C. Moller, and G. W. Kreutzberg, “Inhibition of posttraumatic microglial proliferation in a genetic model of macrophage colony-stimulating factor deficiency in the mouse,” European Journal of Neuroscience, vol. 6, no. 10, pp. 1615–1618, 1994. View at: Publisher Site | Google Scholar
  164. H. Cardenas and L. M. Bolin, “Compromised reactive microgliosis in MPTP-lesioned IL-6 KO mice,” Brain Research, vol. 985, no. 1, pp. 89–97, 2003. View at: Publisher Site | Google Scholar
  165. D. S. Tian, M. J. Xie, Z. Y. Yu et al., “Cell cycle inhibition attenuates microglia induced inflammatory response and alleviates neuronal cell death after spinal cord injury in rats,” Brain Research, vol. 1135, no. 1, pp. 177–185, 2007. View at: Publisher Site | Google Scholar
  166. V. Raghavendra, F. Tanga, and J. A. Deleo, “Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy,” Journal of Pharmacology and Experimental Therapeutics, vol. 306, no. 2, pp. 624–630, 2003. View at: Publisher Site | Google Scholar
  167. L. Spataro, J. Dilgen, S. Retterer et al., “Dexamethasone treatment reduces astroglia responses to inserted neuroprosthetic devices in rat neocortex,” Experimental Neurology, vol. 194, no. 2, pp. 289–300, 2005. View at: Publisher Site | Google Scholar
  168. O. Rapalino, O. Lazarov-Spiegler, E. Agranov et al., “Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats,” Nature Medicine, vol. 4, no. 7, pp. 814–821, 1998. View at: Publisher Site | Google Scholar
  169. Y. Ziv, H. Avidan, S. Pluchino, G. Martino, and M. Schwartz, “Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 35, pp. 13174–13179, 2006. View at: Publisher Site | Google Scholar
  170. R. Mori, T. J. Shaw, and P. Martin, “Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring,” Journal of Experimental Medicine, vol. 205, no. 1, pp. 43–51, 2008. View at: Publisher Site | Google Scholar
  171. R. Mirza, L. A. DiPietro, and T. J. Koh, “Selective and specific macrophage ablation is detrimental to wound healing in mice,” American Journal of Pathology, vol. 175, no. 6, pp. 2454–2462, 2009. View at: Publisher Site | Google Scholar
  172. L. Mori, A. Bellini, M. A. Stacey, M. Schmidt, and S. Mattoli, “Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow,” Experimental Cell Research, vol. 304, no. 1, pp. 81–90, 2005. View at: Publisher Site | Google Scholar
  173. L. Yang, P. G. Scott, C. Dodd et al., “Identification of fibrocytes in postburn hypertrophic scar,” Wound Repair and Regeneration, vol. 13, no. 4, pp. 398–404, 2005. View at: Publisher Site | Google Scholar
  174. M. Nahrendorf, F. K. Swirski, E. Aikawa et al., “The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions,” Journal of Experimental Medicine, vol. 204, no. 12, pp. 3037–3047, 2007. View at: Publisher Site | Google Scholar
  175. S. Hayashidani, H. Tsutsui, T. Shiomi et al., “Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction,” Circulation, vol. 108, no. 17, pp. 2134–2140, 2003. View at: Publisher Site | Google Scholar
  176. T. Hayasaki, K. Kaikita, T. Okuma et al., “CC chemokine receptor-2 deficiency attenuates oxidative stress and infarct size caused by myocardial ischemia-reperfusion in mice,” Circulation Journal, vol. 70, no. 3, pp. 342–351, 2006. View at: Publisher Site | Google Scholar
  177. J. Leor, L. Rozen, A. Zuloff-Shani et al., “Ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart,” Circulation, vol. 114, no. 1, pp. I94–I100, 2006. View at: Publisher Site | Google Scholar
  178. M. J. van Amerongen, M. C. Harmsen, N. van Rooijen, A. H. Petersen, and M. J. A. Van Luyn, “Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice,” American Journal of Pathology, vol. 170, no. 3, pp. 818–829, 2007. View at: Publisher Site | Google Scholar
  179. S. B. Haudek, Y. Xia, P. Huebener et al., “Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 48, pp. 18284–18289, 2006. View at: Publisher Site | Google Scholar
  180. S. Hayashidani, H. Tsutsui, M. Ikeuchi et al., “Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction,” American Journal of Physiology, vol. 285, no. 3, pp. H1229–H1235, 2003. View at: Google Scholar
  181. J. A. Belperio, M. P. Keane, M. D. Burdick et al., “Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome,” The Journal of Clinical Investigation, vol. 108, no. 4, pp. 547–556, 2001. View at: Publisher Site | Google Scholar
  182. J. A. Belperio, M. P. Keane, M. D. Burdick et al., “Critical role for CXCR3 chemokine biology in the pathogenesis of bronchiolitis obliterans syndrome,” Journal of Immunology, vol. 169, no. 2, pp. 1037–1049, 2002. View at: Google Scholar
  183. Z. Xing, G. M. Tremblay, P. J. Sime, and J. Gauldie, “Overexpression of granulocyte-macrophage colony-stimulating factor induces pulmonary granulation tissue formation and fibrosis by induction of transforming growth factor-β1 and myofibroblast accumulation,” American Journal of Pathology, vol. 150, no. 1, pp. 59–66, 1997. View at: Google Scholar
  184. K. Atabai, S. Jame, N. Azhar et al., “Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages,” The Journal of Clinical Investigation, vol. 119, no. 12, pp. 3713–3722, 2009. View at: Publisher Site | Google Scholar
  185. M. D. Burdick, L. A. Murray, M. P. Keane et al., “CXCCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling,” American Journal of Respiratory and Critical Care Medicine, vol. 171, no. 3, pp. 261–268, 2005. View at: Publisher Site | Google Scholar
  186. F. Marra, R. DeFranco, C. Grappone et al., “Expression of monocyte chemotactic protein-1 precedes monocyte recruitment in a rat model of acute liver injury, and is modulated by vitamin E,” Journal of Investigative Medicine, vol. 47, no. 1, pp. 66–75, 1999. View at: Google Scholar
  187. K. Otogawa, K. Kinoshita, H. Fujii et al., “Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: implications for the pathogenesis of human nonalcoholic steatohepatitis,” American Journal of Pathology, vol. 170, no. 3, pp. 967–980, 2007. View at: Publisher Site | Google Scholar
  188. W. Jiang, R. Sun, H. Wei, and Z. Tian, “Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 47, pp. 17077–17082, 2005. View at: Publisher Site | Google Scholar
  189. J. P. Iredale, R. C. Benyon, J. Pickering et al., “Mechanisms of spontaneous resolution of rat liver fibrosis: hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors,” The Journal of Clinical Investigation, vol. 102, no. 3, pp. 538–549, 1998. View at: Google Scholar
  190. C. Mitchell, D. Couton, J. P. Couty et al., “Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice,” American Journal of Pathology, vol. 174, no. 5, pp. 1766–1775, 2009. View at: Publisher Site | Google Scholar
  191. M. Ide, M. Kuwamura, T. Kotani, O. Sawamoto, and J. Yamate, “Effects of gadolinium chloride (GdCl3) on the appearance of macrophage populations and fibrogenesis in thioacetamide-induced rat hepatic lesions,” Journal of Comparative Pathology, vol. 133, no. 2-3, pp. 92–102, 2005. View at: Publisher Site | Google Scholar
  192. T. Kisseleva, H. Uchinami, N. Feirt et al., “Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis,” Journal of Hepatology, vol. 45, no. 3, pp. 429–438, 2006. View at: Publisher Site | Google Scholar
  193. J. T. Pesce, T. R. Ramalingam, M. M. Mentink-Kane et al., “Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis,” PLoS Pathogens, vol. 5, no. 4, Article ID e1000371, 2009. View at: Publisher Site | Google Scholar
  194. J. A. Thomas, C. Pope, D. Wojtacha et al., “Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function,” Hepatology, vol. 53, no. 6, pp. 2003–2015, 2011. View at: Publisher Site | Google Scholar
  195. Y. Popov, D. Y. Sverdlov, K. R. Bhaskar et al., “Macrophage-mediated phagocytosis of apoptotic cholangiocytes contributes to reversal of experimental biliary fibrosis,” American Journal of Physiology, vol. 298, no. 3, pp. G323–G334, 2010. View at: Publisher Site | Google Scholar
  196. H. J. Anders, M. Frink, Y. Linde et al., “CC chemokine ligand 5/RANTES chemokine antagonists aggravate glomerulonephritis despite reduction of glomerular leukocyte infiltration,” Journal of Immunology, vol. 170, no. 11, pp. 5658–5666, 2003. View at: Google Scholar
  197. A. P. Castaño, S. L. Lin, T. Surowy et al., “Serum amyloid P inhibits fibrosis through Fc gamma R-dependent monocyte-macrophage regulation in vivo,” Science Translational Medicine, vol. 1, no. 5, p. 5ra13, 2009. View at: Publisher Site | Google Scholar
  198. V. Ninichuk, A. G. Khandoga, S. Segerer et al., “The role of interstitial macrophages in nephropathy of type 2 diabetic db/db mice,” American Journal of Pathology, vol. 170, no. 4, pp. 1267–1276, 2007. View at: Publisher Site | Google Scholar
  199. S. Dehmel, S. Wang, C. Schmidt et al., “Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long-term renal allograft outcome,” European Journal of Immunology, vol. 40, no. 1, pp. 267–278, 2010. View at: Publisher Site | Google Scholar
  200. T. Wada, N. Sakai, Y. Sakai, K. Matsushima, S. Kaneko, and K. Furuichi, “Involvement of bone-marrow-derived cells in kidney fibrosis,” Clinical and Experimental Nephrology, vol. 15, no. 1, pp. 8–13, 2011. View at: Publisher Site | Google Scholar
  201. M. Broekema, M. C. Harmsen, M. J. A. van Luyn et al., “Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats,” Journal of the American Society of Nephrology, vol. 18, no. 1, pp. 165–175, 2007. View at: Publisher Site | Google Scholar
  202. M. Zeisberg, J. I. Hanai, H. Sugimoto et al., “BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury,” Nature Medicine, vol. 9, no. 7, pp. 964–968, 2003. View at: Publisher Site | Google Scholar
  203. M. Zeisberg, M. Khurana, V. H. Rao et al., “Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease,” PLoS Medicine, vol. 3, no. 4, article e100, 2006. View at: Publisher Site | Google Scholar
  204. M. Nishida, Y. Okumura, S. I. Fujimoto, I. Shiraishi, T. Itoi, and K. Hamaoka, “Adoptive transfer of macrophages ameliorates renal fibrosis in mice,” Biochemical and Biophysical Research Communications, vol. 332, no. 1, pp. 11–16, 2005. View at: Publisher Site | Google Scholar

Copyright © 2012 Maciej Lech et al. 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.

3471 Views | 1612 Downloads | 46 Citations
PDF Download Citation Citation
Download other formatsMore
ePub
XML
Order printed copiesOrder

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19.