Pathophysiological Role of Extracellular Purinergic Mediators in the Control of Intestinal Inflammation

Kurashima, Yosuke; Kiyono, Hiroshi; Kunisawa, Jun

doi:https://doi.org/10.1155/2015/427125

Mediators of Inflammation

On this page

Abstract Acknowledgments References Copyright Related Articles

Special Issue

Mediators of Gut Mucosal Immunity and Inflammation

View this Special Issue

Review Article | Open Access

Volume 2015 | Article ID 427125 | https://doi.org/10.1155/2015/427125

Pathophysiological Role of Extracellular Purinergic Mediators in the Control of Intestinal Inflammation

Yosuke Kurashima,^1,2,3Hiroshi Kiyono,^2,3,4and Jun Kunisawa^1,2,4,5,6

Academic Editor: Ishak O. Tekin

Received05 Aug 2014

Accepted30 Sept 2014

Published07 Apr 2015

Abstract

Purinergic mediators such as adenosine 5′-triphosphate (ATP) are released into the extracellular compartment from damaged tissues and activated immune cells. They are then recognized by multiple purinergic P2X and P2Y receptors. Release and recognition of extracellular ATP are associated with both the development and the resolution of inflammation and infection. Accumulating evidence has recently suggested the potential of purinergic receptors as novel targets for drugs for treating intestinal disorders, including intestinal inflammation and irritable bowel syndrome. In this review, we highlight recent findings regarding the pathophysiological role of purinergic mediators in the development of intestinal inflammation.

1. General Features and Metabolism of ATP in the Intestinal Compartment

Damage, trauma, and pathogenic infection cause inflammatory responses in tissues. Clinical pathologic responses involve the release of a series of inflammatory mediators, including cytokines (e.g., IL-1β, IL-6, and TNFα), lipid mediators (e.g., leukotrienes, platelet activating factor, and prostaglandins), and chemical mediators (e.g., histamine).

Accumulating evidence clearly demonstrates the importance of purinergic mediators, especially adenosine 5′-triphosphate (ATP), in the development of various inflammatory disorders [1]. In general, ATP is generated during glycolysis and the tricarboxylic acid cycle in the intracellular compartment and acts as an energy source. However, ATP is occasionally released into the extracellular compartment as so-called extracellular ATP (eATP). Biological roles of eATP were first reported in synaptic neurotransmission and neuromodulation [2]. eATP is released from nerves as a transmitter or cotransmitter and causes pain [2]. In the intestine, purinergic signaling is important for synaptic transmission in the enteric nervous system [2]. The excitatory postsynaptic potential of myenteric neurons is mediated by eATP together with nicotinic acetylcholine [3, 4]. Thus, stimulation by eATP is important for maintaining physiological intestinal motility.

In addition to nerve cells, dead, activated, or infected cells release eATP, recruiting and activating both innate and acquired immunity [5]. For instance, bacterial stimulation leads to eATP release from monocytes and enhances the production of cytokines in an autocrine manner [6]. Some gap junction hemichannels, such as pannexin and connexin hemichannels, are important for ATP release during cell activation [7]. In the steady state intestine some commensal bacteria also have the potential to release eATP [8]; thus, germ-free mice have lower luminal ATP levels than do specific pathogen-free mice. This commensal-derived eATP stimulates CD70⁺ CD11 cells in the intestinal compartment and recruits Th17 cells into the colon [9].

Hydrolysis of the released eATP is catalyzed by cell surface-located enzymes, such as ectonucleoside triphosphate diphosphohydrolase family enzymes (e.g., e-NTPDase I (CD39), ectonucleotidase, and NT5E (CD73)). Consistent with the activity of eATP in the induction of intestinal Th17 cells, a deficiency of eATP-degrading enzymes elevates the concentration of luminal eATP and subsequently enhances the generation of Th17 cells in the gut [10]. By the sequential enzymatic activity of CD39 and CD73, eATP is hydrolyzed to adenosine in the extracellular compartment [11] (Figure 1). Finally, adenosine is metabolized by two pathways: one is intracellular uptake by equilibrative nucleoside transporters and the other is metabolism to AMP or inosine by adenosine kinase and adenosine deaminase, respectively [11].

Recognition of eATP is mediated by purinergic receptors, which comprise P2X (P2X_1–7) and P2Y receptors (). P2X_1–7 receptors are ATP-gated ion channels and are specific for ATP, whereas P2Y receptors are G protein-coupled receptors that are specific for ADP, UTP, and ATP [5]. Each eATP-specific purinergic receptor requires a different concentration of eATP for activation. For instance, activation of P2X₇ receptors requires a high concentration (mM level) of eATP, whereas other P2X receptors require lower concentrations (nM to μM) [5]. In addition, heterooligomeric assembly occurs within P2X receptor subunits (e.g., P2X_1–3, P2X_1–4, and ) and alters their functional properties, providing versatile signaling pathways mediated by eATP [12, 13].

Among several P2X and P2Y receptors, P2X₇ is involved mainly in the induction of inflammatory responses. P2X₇ uniquely has 200 amino acid residues in its C-terminus, which is longer than that of other P2X receptors [14]. C-terminal residues are important for receptor localization at the cell surface [14]. Stimulation of P2X₇ by prolonged high concentrations of eATP induces pore formation in the cell membrane and increases membrane permeability [14, 15]. These pores allow influx and efflux of particles with molecular masses of up to 800 Da [11]. These changes also mediate the production of reactive oxygen species and activate inflammasome, a key molecule in the production of inflammatory cytokines such as IL-1β and IL-18 [5] that is responsible for inducing inflammatory responses. In addition, eATP-P2X₇ pathways are involved in molecular shedding. Molecules responsible for adhesion (e.g., CD44 and CD62L) are shed from the cell surface by P2X₇ activation; stimulation by eATP is thus involved in cell migration [16, 17].

2. Role of eATP in Prevention and Development of Infectious Diseases

Some kinds of pathogens use intestinal tissues as invasion sites. Upon infection, pathogenic components from the microorganisms stimulate innate immune cells such as macrophages and neutrophils via innate receptors such as toll-like receptors (TLRs). This stimulation induces the release of eATP through pannexin-1 hemichannels and subsequently activates P2Y₂ and P2X₇ receptors in an autocrine or paracrine manner and enhances cytokine production [6, 18]. In microglial cells and macrophages, initial stimulation of lipopolysaccharide- (LPS-) TLR4 pathways with subsequent signaling by the P2X₇ pathway induces Ca²⁺ influx and IL-1β secretion [19]. In fact, eATP-P2X₇ pathways play important roles in eliminating intracellular pathogens. Activation of P2X₇ by selective agonists induces effective clearance of Toxoplasma gondii from infected macrophages and of chlamydia from epithelial cells [20, 21]. These signals are required for protective immunity against pathogens. In addition, a recent study found that eATP production was induced by administration of vaccine adjuvant, which is required for an effective response in vaccination against infectious agents and cancer [22].

Reciprocally, the pathogenicity of some pathogens is determined by their ability to induce eATP release. For instance, enteropathogenic Escherichia coli induces eATP release from host cells by killing them via type III secretion systems as well as cell-permeable cystic fibrosis transmembrane conductance regulator-mediated pathways [23]. Similarly, cholera toxin from Vibrio cholerae is capable of inducing eATP production [24]. Another study in colon epithelial cell lines found that adenosine, a metabolite of eATP, bound to receptors, resulting in short-circuit current responses causing diarrhea [23, 24].

Some kinds of pathogens have unique systems that inhibit eATP release from host cells and thus prevent the spread of infection to the host’s immune system. For instance, infection of epithelial cells with Shigella flexneri induces eATP release via connexin hemichannels in the early phase of infection, and this release alerts the host to the pathogenic infection. However, prolonged infection with Shigella is accompanied by the production of Ptdlns5P, a lipid mediator, to close the connexin hemichannels [25]. Another example is that of Streptococcus agalactiae, a commensal bacterium that resides in the intestine or vaginal mucosa but occasionally shows pathogenicity, causing neonatal pneumonia. Streptococcus agalactiae releases ecto-5′-nucleoside diphosphate phosphohydrolase and degrades extracellular nucleotides, including eATP; it thus turns off the eATP-mediated alerting of the host defenses to danger [26, 27].

3. Pathological Aspects of eATP in the Mucosal Compartment

eATP-purinergic receptor-mediated pathways are now considered to be targets for the treatment of inflammatory disorders in the systemic compartment, including inflammatory pain and rheumatoid arthritis [28]. Accumulating evidence suggests that eATP-purinergic receptor-mediated pathways are also potential targets for the treatment of inflammatory diseases of mucosal tissues in, for example, the respiratory and gastrointestinal tracts [4, 5, 29]. In the asthma model, migration of eosinophils, dendritic cells, and Th2 cells into the inflamed lung is mediated by the P2Y₂ receptor; therefore, P2Y₂-deficient mice show reduced inflammatory responses [30]. Th2-type immune responses are also induced by dendritic cells expressing P2X₇. Indeed, depletion of eATP by apyrase treatment or P2X₇ deficiency reduces signs of inflammation in the upper respiratory tract [31]. It was recently found that the functional capacity of P2X₇ (i.e., its ability to promote pore formation) is associated with asthma risk or disease severity in humans [32]. Moreover, in vivo imaging analysis has revealed eATP release in the intestinal compartment and peritoneal cavity of mice with acute graft-versus-host disease (GVHD) [33]. Treatment with apyrase or with inhibitors of various purinergic receptors inhibits GVHD-associated intestinal inflammation. In this case, the eATP-P2X7 pathway activates dendritic cells and consequently induces Th1 immune responses (e.g., IFNγ production) and expansion of donor T cells, thus contributing to the onset of inflammation.

Several studies have revealed the pathologic roles of eATP and purinergic receptors (especially P2X₇) in the development of intestinal disorders, including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) [1, 34] (Table 1). IBS is a common gastrointestinal disorder characterized by discomfort, chronic abdominal pain, and altered bowel habit. Sometimes it occurs after intestinal infection. One meta-analysis has demonstrated that the risk of IBS increases 600% after gastrointestinal infection [35]. Consistently, it has been reported that transient intestinal infection with Trichinella spiralis in mice causes postinflammatory visceral hypersensitivity, which is associated with IL-1β production mediated by eATP-P2X₇ pathways [34] (Table 1). Because mast cells are considered to play a critical role in the development of IBS and express high levels of P2X₇, it is possible that the eATP-P2X₇ pathway in mast cells is involved in the development of IBS [36].

The eATP-purinergic receptor pathway, especially the eATP-P2X₇ pathway, is also involved in the development of IBD. Overexpression of P2X₇ receptors has been observed in the intestinal mucosa of patients with IBD—especially Crohn’s disease [44]. Experimentally, P2X₇-deficient mice do not develop experimental colitis, and inhibition of P2X₇ by A-740003, Brilliant Blue G, or KN-62 ameliorates experimental colitis by reducing the recruitment of neutrophils, T cells, and macrophages, as well as collagen deposition [44] (Table 1). The eATP-P2X7 pathway is therefore now considered to be a novel therapeutic target in the treatment of IBD [43, 44] (Table 1).

Several mechanisms of eATP-mediated inflammation in the development of IBD have been proposed. First, eATP from damaged intestinal epithelial cells, which are frequently observed in IBD patients, and inflammatory cells (e.g., neutrophils and macrophages) stimulates dendritic cells to produce IL-6, IL-12, and IL-23 and TGFβ, thus inducing the production of inflammatory Th1 and Th17 cells [42, 43] (Figure 2) (Table 1). Enteric neuronal cell death is frequently observed in intestinal inflammation and causes colonic motor dysfunction. The eATP–P2X7 pathway is involved in enteric neuronal cell death through the pannexin-inflammasome cascade, and thus colonic motor dysfunction during colitis is prevented by targeting these pathways [41] (Table 1). We previously established mast cell-specific antibody libraries and showed that P2X₇ is expressed at high levels in mast cells in the colonic tissues [40]. eATP stimulates mast cells to induce the production of inflammatory chemokines (e.g., CCL2, CCL4, CCL7, CXCL1, and CXCL2), cytokines (IL-1β, IL-6, and TNFα), and mediators (histamines and leukotriene). Thus, blockade of P2X₇ by a specific antibody (1F11 monoclonal antibody) inhibits mast cell activation in the colonic tissues and consequently prevents the development of intestinal inflammation [40] (Table 1). In this pathway, P2X₇ expression on mast cells is important for the development of colitis, because mast cell-deficient mice reconstituted with P2X₇-deficient mast cells show amelioration of inflammatory signs. Of clinical relevance, we have found that the number of P2X₇⁺ mast cells is increased at sites of inflammation in Crohn’s disease patients [40]. eATP is produced by injured epithelial cells and inflammatory cells, including neutrophils, via gap junction molecules such as connexin 43 [45]. It was reported that P2Y2 and P2X7 receptors are important for the migration of neutrophils and macrophages. In the inflammatory condition, neutrophils transmigrated between epithelial cells to the luminal part of the intestine. In this condition, platelets translocate along with neutrophils and released eATP at the mucosal surface (Figure 2) (Table 1). Additionally, mast cells express ectoadenylate kinase and ATP synthase to mediate the extracellular conversion of ADP to ATP, which in turn promotes mast cell activation in an autocrine and paracrine manner (Figure 2). We have recently found that, in contrast to the abundance of P2X₇ expression on mast cells in the colon, there are limited levels of P2X₇ expression on skin mast cells, which is regulated by skin fibroblasts [46]. Skin fibroblasts uniquely express Cyp26b1 to degrade retinoic acid within tissues or microenvironments; Cyp26b1 is responsible for inhibiting P2X₇ expression [46]. Thus, unique tissue environments determine P2X₇ expression on mast cells, which is a critical factor in the development of local inflammation.

Figure 2

In the intestinal compartment, extracellular ATP (eATP) is released from damaged epithelial cells and commensal bacteria. Macrophages, platelets, mast cells, and neutrophils are potential source of eATP upon their activation. Neutrophils facilitate translocation of platelets across intestinal epithelium. eATP also induces Th17 cell generation, activation of mast cells, and neuronal cell death, promoting intestinal inflammation. APCs: antigen-presenting cells. eATP stimulates mast cells to induce the production of inflammatory chemokines (e.g., CCL2, CCL4, CCL7, CXCL1, and CXCL2), cytokines (IL-1β, IL-6, and TNFα), and mediators (histamines and leukotrienes).

4. Resolution of eATP-Mediated Inflammation for Maintenance of Mucosal Homeostasis

Once eATP is released, it is soon hydrolyzed to ADP, AMP, and adenosine by the ectonucleotidases CD39 and CD73; this is essential for resolving inflammatory responses (Figure 1). Indeed, CD39-deficient mice, as well as humans who have CD39 polymorphism and thus low levels of CD39 expression, have increased susceptibility to IBD [47]. Similarly, CD73 deficiency or administration of CD73 inhibitor (e.g., α,β-methylene ADP) enhances susceptibility to intestinal inflammation in mice [48–50].

Adenosine, which is derived from the dephosphorylation of eATP via CD39 and CD73 or diffuses directly from the intracellular compartment via equilibrative nucleoside transporters, binds to adenosine receptors such as and A₃ receptors, which are involved in both the promotion and the resolution of inflammatory responses [51–53]. and A₃ receptor expression on T cells and myeloid cells is a prerequisite for the inhibition of intestinal inflammation [54]. In fact, and A₃ adenosine receptor-selective agonists (e.g., ATP-146e and IB-MECA, resp.) ameliorate intestinal inflammation by impairing the recruitment of inflammatory cells and the production of inflammatory cytokines [55, 56]. In addition, cyclosporine, salicylates, methotrexate, and sulfasalazine, which are used to treat IBD in humans, all decrease eATP levels and increase adenosine production, partly via the stimulation of CD73-dependent adenosine production [57]. Similarly, upregulation of CD39 expression induced on dendritic cells by IL-27 hampers Th1 and Th17 cell production and consequently prevents eATP-mediated inflammation [58]. All of this evidence indicates that inhibition of eATP signaling, together with the promotion of adenosine-mediated regulatory pathways by targeting receptors or ectoenzymes, would be a beneficial strategy for the treatment of intestinal inflammation.

5. Closing Remarks

The importance of purinergic signaling was recognized almost 70 years ago. Accumulating evidence has since revealed the underlying molecular and cellular mechanisms of purinergic signal-mediated maintenance and disruption of mucosal homeostasis. Currently, the clinical relevance of some of the drugs used to treat intestinal inflammation is explained by their regulation of eATP-adenosine balance. Additionally, drugs that target purinergic receptors have now undergone clinical trials [11]. Notably, ATP-adenosine balance, as well as receptor expression levels and the cells expressing these receptors, differs among tissues and environmental conditions. Further investigations using new technologies such as in vivo monitoring of eATP release [59, 60] will clarify the complex mechanisms of purinergic signal-mediated immune regulation. This in turn will provide further advances in the design of drugs for preventing and treating inflammatory diseases and maintaining immunologic health.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

Some of the work featured in this review article was supported by grants from the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries, and the Food Industry; the Program for Promotion of Basic and Applied Research for Innovations in Bio-Oriented Industry; Japan Science and Technology Agency’s Core Research for Evolutional Science and Technology (CREST); the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Ministry of Health and Welfare of Japan; the Yakult Bio-Science Foundation; Kowa Life Science Foundation; a Kishimoto Foundation Research Grant; and The Naito Foundation.

References

M. Idzko, D. Ferrari, and H. K. Eltzschig, “Nucleotide signalling during inflammation,” Nature, vol. 509, no. 7500, pp. 310–317, 2014.
View at: Publisher Site | Google Scholar
G. Burnstock, “Purinergic signalling and disorders of the central nervous system,” Nature Reviews Drug Discovery, vol. 7, no. 7, pp. 575–590, 2008.
View at: Publisher Site | Google Scholar
G. Burnstock, “The journey to establish purinergic signalling in the gut,” Neurogastroenterology and Motility, vol. 20, no. 1, pp. 8–19, 2008.
View at: Publisher Site | Google Scholar
J. A. Roberts, M. K. Lukewich, K. A. Sharkey, J. B. Furness, G. M. Mawe, and A. E. Lomax, “The roles of purinergic signaling during gastrointestinal inflammation,” Current Opinion in Pharmacology, vol. 12, no. 6, pp. 659–666, 2012.
View at: Publisher Site | Google Scholar
W. G. Junger, “Immune cell regulation by autocrine purinergic signalling,” Nature Reviews Immunology, vol. 11, no. 3, pp. 201–212, 2011.
View at: Publisher Site | Google Scholar
A. Piccini, S. Carta, S. Tassi, D. Lasiglié, G. Fossati, and A. Rubartelli, “ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 23, pp. 8067–8072, 2008.
View at: Publisher Site | Google Scholar
S. E. Adamson and N. Leitinger, “The role of pannexin1 in the induction and resolution of inflammation,” FEBS Letters, vol. 588, no. 8, pp. 1416–1422, 2014.
View at: Publisher Site | Google Scholar
T. Iwase, H. Shinji, A. Tajima et al., “Isolation and identification of ATP-secreting bacteria from mice and humans,” Journal of Clinical Microbiology, vol. 48, no. 5, pp. 1949–1951, 2010.
View at: Publisher Site | Google Scholar
K. Atarashi, J. Nishimura, T. Shima et al., “ATP drives lamina propria T_H17 cell differentiation,” Nature, vol. 455, no. 7214, pp. 808–812, 2008.
View at: Publisher Site | Google Scholar
T. Kusu, H. Kayama, M. Kinoshita et al., “Ecto-nucleoside triphosphate diphosphohydrolase 7 controls Th17 cell responses through regulation of luminal ATP in the small intestine,” Journal of Immunology, vol. 190, no. 2, pp. 774–783, 2013.
View at: Publisher Site | Google Scholar
H. K. Eltzschig, M. V. Sitkovsky, and S. C. Robson, “Purinergic signaling during inflammation,” The New England Journal of Medicine, vol. 367, no. 24, pp. 2322–2333, 2012.
View at: Publisher Site | Google Scholar
L.-H. Jiang, M. Kim, V. Spelta, X. Bo, A. Surprenant, and R. A. North, “Subunit arrangement in P2X receptors,” The Journal of Neuroscience, vol. 23, no. 26, pp. 8903–8910, 2003.
View at: Google Scholar
G. E. Torres, T. M. Egan, and M. M. Voigt, “Hetero-oligomeric assembly of P2X receptor subunits. Specificities exist with regard to possible partners,” The Journal of Biological Chemistry, vol. 274, no. 10, pp. 6653–6659, 1999.
View at: Publisher Site | Google Scholar
H. M. Costa-Junior, F. S. Vieira, and R. Coutinho-Silva, “C terminus of the P2X7 receptor: treasure hunting,” Purinergic Signalling, vol. 7, no. 1, pp. 7–19, 2011.
View at: Publisher Site | Google Scholar
H. L. Wilson, S. A. Wilson, A. Surprenant, and R. North, “Epithelial membrane proteins induce membrane blebbing and interact with the P2X7 receptor C terminus,” The Journal of Biological Chemistry, vol. 277, no. 37, pp. 34017–34023, 2002.
View at: Publisher Site | Google Scholar
F. Scheuplein, N. Schwarz, S. Adriouch et al., “NAD+ and ATP released from injured cells induce P2X 7-dependent shedding of CD62L and externalization of phosphatidylserine by Murine T cells,” Journal of Immunology, vol. 182, no. 5, pp. 2898–2908, 2009.
View at: Publisher Site | Google Scholar
C. Lin, S. Ren, L. Zhang, H. Jin, J. Sun, and Y. Zuo, “Extracellular ATP induces CD44 shedding from macrophage-like P388D1 cells via the P2X7 receptor,” Hematological Oncology, vol. 30, no. 2, pp. 70–75, 2012.
View at: Publisher Site | Google Scholar
Y. Chen, Y. Yao, Y. Sumi et al., “Purinergic signaling: a fundamental mechanism in neutrophil activation,” Science Signaling, vol. 3, no. 125, p. ra45, 2010.
View at: Publisher Site | Google Scholar
D. Ferrari, P. Chiozzi, S. Falzoni, S. Hanau, and F. Di Virgilio, “Purinergic modulation of interleukin-1β release from microglial cells stimulated with bacterial endotoxin,” Journal of Experimental Medicine, vol. 185, no. 3, pp. 579–582, 1997.
View at: Publisher Site | Google Scholar
G. Corrêa, C. Marques da Silva, A. C. de Abreu Moreira-Souza, R. C. Vommaro, and R. Coutinho-Silva, “Activation of the P2X₇ receptor triggers the elimination of Toxoplasma gondii tachyzoites from infected macrophages,” Microbes and Infection, vol. 12, no. 6, pp. 497–504, 2010.
View at: Publisher Site | Google Scholar
T. Darville, L. Welter-Stahl, C. Cruz, A. A. Sater, C. W. Andrews Jr., and D. M. Ojcius, “Effect of the purinergic receptor P2X₇ on Chlamydia infection in cervical epithelial cells and vaginally infected mice,” The Journal of Immunology, vol. 179, no. 6, pp. 3707–3714, 2007.
View at: Publisher Site | Google Scholar
M. Vono, M. Taccone, P. Caccin et al., “The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 52, pp. 21095–21100, 2013.
View at: Publisher Site | Google Scholar
J. K. Crane, R. A. Olson, H. M. Jones, and M. E. Duffey, “Release of ATP during host cell killing by enteropathogenic E. coli and its role as a secretory mediator,” American Journal of Physiology: Gastrointestinal and Liver Physiology, vol. 283, no. 1, pp. G74–G86, 2002.
View at: Google Scholar
J. K. Crane, T. M. Naeher, S. S. Choudhari, and E. M. Giroux, “Two pathways for ATP release from host cells in enteropathogenic Escherichia coli infection,” American Journal of Physiology: Gastrointestinal and Liver Physiology, vol. 289, no. 3, pp. G407–G417, 2005.
View at: Publisher Site | Google Scholar
A. Puhar, H. Tronchère, B. Payrastre, G. Tran van Nhieu, and P. J. Sansonetti, “A Shigella effector dampens inflammation by regulating epithelial release of danger signal ATP through production of the lipid mediator PtdIns5P,” Immunity, vol. 39, no. 6, pp. 1121–1131, 2013.
View at: Publisher Site | Google Scholar
A. Firon, M. Dinis, B. Raynal, C. Poyart, P. Trieu-Cuot, and P. A. Kaminski, “Extracellular nucleotide catabolism by the Group B Streptococcus ectonucleotidase NudP increases bacterial survival in blood,” The Journal of Biological Chemistry, vol. 289, no. 9, pp. 5479–5489, 2014.
View at: Publisher Site | Google Scholar
R. Coutinho-Silva and D. M. Ojcius, “Role of extracellular nucleotides in the immune response against intracellular bacteria and protozoan parasites,” Microbes and Infection, vol. 14, no. 14, pp. 1271–1277, 2012.
View at: Publisher Site | Google Scholar
S. Brumfield, J. J. Matasi, D. Tulshian et al., “Synthesis and SAR development of novel P2X7 receptor antagonists for the treatment of pain: part 2,” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 24, pp. 7287–7290, 2011.
View at: Publisher Site | Google Scholar
L. Antonioli, R. Colucci, C. Pellegrini et al., “The role of purinergic pathways in the pathophysiology of gut diseases: pharmacological modulation and potential therapeutic applications,” Pharmacology & Therapeutics, vol. 139, no. 2, pp. 157–188, 2013.
View at: Publisher Site | Google Scholar
T. Müller, B. Robaye, R. P. Vieira et al., “The purinergic receptor P2Y2 receptor mediates chemotaxis of dendritic cells and eosinophils in allergic lung inflammation,” Allergy, vol. 65, no. 12, pp. 1545–1553, 2010.
View at: Publisher Site | Google Scholar
T. Müller, R. P. Vieira, M. Grimm et al., “A potential role for P2X₇R in allergic airway inflammation in mice and humans,” American Journal of Respiratory Cell and Molecular Biology, vol. 44, no. 4, pp. 456–464, 2011.
View at: Publisher Site | Google Scholar
D. M. Manthei, D. J. Jackson, M. D. Evans et al., “Protection from asthma in a high-risk birth cohort by attenuated P2X 7 function,” Journal of Allergy and Clinical Immunology, vol. 130, no. 2, pp. 496–502, 2012.
View at: Publisher Site | Google Scholar
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. 1434–1439, 2010.
View at: Publisher Site | Google Scholar
C. Keating, P. Pelegrin, C. M. Martínez, and D. Grundy, “P2X₇ receptor-dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome,” The Journal of Immunology, vol. 187, no. 3, pp. 1467–1474, 2011.
View at: Publisher Site | Google Scholar
M. Thabane, D. T. Kottachchi, and J. K. Marshall, “Systematic review and meta-analysis: the incidence and prognosis of post-infectious irritable bowel syndrome,” Alimentary Pharmacology & Therapeutics, vol. 26, no. 4, pp. 535–544, 2007.
View at: Publisher Site | Google Scholar
L. Ohman and M. Simren, “Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions,” Nature Reviews Gastroenterology & Hepatology, vol. 7, no. 3, pp. 163–173, 2010.
View at: Google Scholar
T. Weissmüller, E. L. Campbell, P. Rosenberger et al., “PMNs facilitate translocation of platelets across human and mouse epithelium and together alter fluid homeostasis via epithelial cell-expressed ecto-NTPDases,” Journal of Clinical Investigation, vol. 118, no. 11, pp. 3682–3692, 2008.
View at: Publisher Site | Google Scholar
U. Schenk, A. M. Westendorf, E. Radaelli et al., “Purinergic control of T cell activation by ATP released through pannexin-1 hemichannels,” Science Signaling, vol. 1, no. 39, article ra6, 2008.
View at: Publisher Site | Google Scholar
E. Degagné, J. Degrandmaison, D. M. Grbic, V. Vinette, G. Arguin, and F.-P. Gendron, “P2Y2 receptor promotes intestinal microtubule stabilization and mucosal re-epithelization in experimental colitis,” Journal of Cellular Physiology, vol. 228, no. 1, pp. 99–109, 2013.
View at: Publisher Site | Google Scholar
Y. Kurashima, T. Amiya, T. Nochi et al., “Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors,” Nature Communications, vol. 3, article 1034, 2012.
View at: Publisher Site | Google Scholar
B. D. Gulbransen, M. Bashashati, S. A. Hirota et al., “Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis,” Nature Medicine, vol. 18, no. 4, pp. 600–604, 2012.
View at: Publisher Site | Google Scholar
Y. Yao, M. K. Levings, and T. S. Steiner, “ATP conditions intestinal epithelial cells to an inflammatory state that promotes components of DC maturation,” European Journal of Immunology, vol. 42, no. 12, pp. 3310–3321, 2012.
View at: Publisher Site | Google Scholar
C. C. Marques, M. T. Castelo-Branco, R. G. Pacheco et al., “Prophylactic systemic P2X7 receptor blockade prevents experimental colitis,” Biochimica et Biophysica Acta: Molecular Basis of Disease, vol. 1842, no. 1, pp. 65–78, 2014.
View at: Publisher Site | Google Scholar
A. R. Neves, M. T. L. Castelo-Branco, V. R. Figliuolo et al., “Overexpression of ATP-activated P2X7 receptors in the intestinal mucosa is implicated in the pathogenesis of Crohn's disease,” Inflammatory Bowel Diseases, vol. 20, no. 3, pp. 444–457, 2014.
View at: Publisher Site | Google Scholar
H. K. Eltzschig, T. Eckle, A. Mager et al., “ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function,” Circulation Research, vol. 99, no. 10, pp. 1100–1108, 2006.
View at: Publisher Site | Google Scholar
Y. Kurashima, T. Amiya, K. Fujisawa et al., “The Enzyme Cyp26b1 mediates inhibition of mast cell activation by fibroblasts to maintain skin-barrier homeostasis,” Immunity, vol. 40, no. 4, pp. 530–541, 2014.
View at: Publisher Site | Google Scholar
D. J. Friedman, B. M. Künzli, Y. I. A-Rahim et al., “CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 39, pp. 16788–16793, 2009.
View at: Publisher Site | Google Scholar
M. S. Bynoe, A. T. Waickman, D. A. Mahamed, C. Mueller, J. H. Mills, and A. Czopik, “CD73 is critical for the resolution of murine colonic inflammation,” Journal of Biomedicine and Biotechnology, vol. 2012, Article ID 260983, 13 pages, 2012.
View at: Publisher Site | Google Scholar
N. A. Louis, A. M. Robinson, C. F. MacManus, J. Karhausen, M. Scully, and S. P. Colgan, “Control of IFN-αA by CD73: implications for mucosal inflammation,” The Journal of Immunology, vol. 180, no. 6, pp. 4246–4255, 2008.
View at: Publisher Site | Google Scholar
K. Synnestvedt, G. T. Furuta, K. M. Comerford et al., “Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia,” Journal of Clinical Investigation, vol. 110, no. 7, pp. 993–1002, 2002.
View at: Publisher Site | Google Scholar
S. P. Colgan and H. K. Eltzschig, “Adenosine and hypoxia-inducible factor signaling in intestinal injury and recovery,” Annual Review of Physiology, vol. 74, pp. 153–175, 2012.
View at: Publisher Site | Google Scholar
L. Antonioli, P. Pacher, E. S. Vizi, and G. Haskó, “CD39 and CD73 in immunity and inflammation,” Trends in Molecular Medicine, vol. 19, no. 6, pp. 355–367, 2013.
View at: Publisher Site | Google Scholar
L. Antonioli, R. Colucci, C. la Motta et al., “Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders,” Current Drug Targets, vol. 13, no. 6, pp. 842–862, 2012.
View at: Publisher Site | Google Scholar
J. H. Ye and V. M. Rajendran, “Adenosine: an immune modulator of inflammatory bowel diseases,” World Journal of Gastroenterology, vol. 15, no. 36, pp. 4491–4498, 2009.
View at: Publisher Site | Google Scholar
M. Odashima, G. Bamias, J. Rivera-Nieves et al., “Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease,” Gastroenterology, vol. 129, no. 1, pp. 26–33, 2005.
View at: Publisher Site | Google Scholar
C. C. Kurtz, “Extracellular adenosine regulates colitis through effects on lymphoid and nonlymphoid cells,” The American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 307, no. 3, pp. G338–G346, 2014.
View at: Google Scholar
F. Ochoa-Cortes, A. Liñán-Rico, K. A. Jacobson, and F. L. Christofi, “Potential for developing purinergic drugs for gastrointestinal diseases,” Inflammatory Bowel Disease, vol. 20, no. 7, pp. 1259–1287, 2014.
View at: Google Scholar
I. D. Mascanfroni, A. Yeste, S. M. Vieira et al., “IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39,” Nature Immunology, vol. 14, no. 10, pp. 1054–1063, 2013.
View at: Publisher Site | Google Scholar
T. Takahashi, Y. Kimura, K. Niwa et al., “In vivo imaging demonstrates ATP release from murine keratinocytes and its involvement in cutaneous inflammation after tape stripping,” Journal of Investigative Dermatology, vol. 133, no. 10, pp. 2407–2415, 2013.
View at: Publisher Site | Google Scholar
P. Pellegatti, L. Raffaghello, G. Bianchi, F. Piccardi, V. Pistoia, and F. Di Virgilio, “Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase,” PLoS ONE, vol. 3, no. 7, Article ID e2599, 2008.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2015 Yosuke Kurashima 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.

PDF Download Citation

Download other formats

Order printed copies

Views

2273

Downloads

1139

Citations