Skip to main content

Advertisement

SpringerLink
Log in

The role of P2X7 receptors in tissue fibrosis: a brief review

  • Review Article
  • Published:
Purinergic Signalling Aims and scope Submit manuscript

Abstract

Many previous studies have demonstrated that P2X7 receptors (P2X7Rs) have a pleiotropic function in different pathological conditions and could represent a novel target for the treatment of a range of diseases. In particular, recent studies have explored the role of P2X7R in fibrosis, the pathological outcome of most chronic inflammatory diseases. The aim of this review is to discuss the biological features of P2X7R and summarize the current knowledge about the putative role of the P2X7R in triggering fibrosis in a wide spectrum of organs such as the lung, kidney, liver, pancreas, and heart.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Corriden R, Insel PA (2010) Basal release of ATP: an autocrine-paracrine mechanism for cell regulation. Sci Signal 3(104):re1

    Article  PubMed Central  PubMed  Google Scholar 

  2. Burnstock G (1972) Purinergic nerves. Pharmacol Rev 24:509–581

    CAS  PubMed  Google Scholar 

  3. Bours MJ, Swennen EL, Di Virgilio F, Cronstein BN, Dagnelie PC (2006) Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol Ther 112(2):358–404

    Article  CAS  PubMed  Google Scholar 

  4. Bours MJ, Dagnelie PC, Giuliani AL, Wesselius A, Di Virgilio F (2011) P2 receptors and extracellular ATP: a novel homeostatic pathway in inflammation. Front Biosci (Schol Ed) 3:1443–1456

    Article  Google Scholar 

  5. Morandini AC, Savio LE, Coutinho-Silva R (2014) The role of p2x7 receptor in infectious inflammatory diseases and the influence of ecto-nucleotidases. Biomedical J 37(4):169–177

    Article  PubMed  Google Scholar 

  6. Yegutkin GG (2014) Enzymes involved in metabolism of extracellular nucleotides and nucleosides: functional implications and measurement of activities. Crit Rev Biochem Mol Biol 49:473–497

    Article  CAS  PubMed  Google Scholar 

  7. Kukulski F, Lévesque SA, Sévigny J (2011) Impact of ectoenzymes on p2 and p1 receptor signaling. Adv Pharmacol 61:263–299

    Article  CAS  PubMed  Google Scholar 

  8. Cronstein BN (2011) Adenosine receptors and fibrosis: a translational review. F1000. Biol Rep 3:21

    Google Scholar 

  9. Lazzerini PE, Natale M, Gianchecchi E et al (2012) Adenosine A2A receptor activation stimulates collagen production in sclerodermic dermal fibroblasts either directly and through a cross-talk with the cannabinoid system. J Mol Med (Berl) 90(3):331–342

    Article  CAS  Google Scholar 

  10. Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492

    CAS  PubMed  Google Scholar 

  11. Buell G, Collo G, Rassendren F (1996) P2X receptors: an emerging channel family. Eur J Neurosci 8(10):2221–2228

    Article  CAS  PubMed  Google Scholar 

  12. Evans RJ, Lewis C, Virginio C et al (1996) Ionic permeability of, and divalent cation effects on, two ATP- gated cation channels (P2X receptors) expressed in mammalian cells. J Physiol 497(Pt 2):413–422

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Burnstock G (2007) Purine and pyrimidine receptors. Cell Mol Life Sci 64:1471–1483

    Article  CAS  PubMed  Google Scholar 

  14. Burnstock G, Knight GE (2004) Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol 240:31–304

    Article  CAS  PubMed  Google Scholar 

  15. Burnstock G (2006) Pathophysiology and therapeutic potential of purinergic signaling. Pharmacol Rev 58(1):58–86

    Article  CAS  PubMed  Google Scholar 

  16. Ferrari D, Pizzirani C, Adinolfi E et al (2006) The P2X7 receptor: a key player in IL-1 processing and release. J Immunol 176(7):3877–3883

    Article  CAS  PubMed  Google Scholar 

  17. Zhou L, Luo L, Qi X, Li X, Gorodeski GI (2009) Regulation of P2X7 gene transcription. Purinergic Signal 5(3):409–426

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Buell GN, Talabot F, Gos A, Lorenz J, Lai E, Morris MA, Antonarakis SE (1998) Gene structure and chromosomal localization of the human P2X7 receptor. Receptors Channels 5(6):347–354

    CAS  PubMed  Google Scholar 

  19. North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82(4):1013–1067

    Article  CAS  PubMed  Google Scholar 

  20. Buell G, Chessell IP, Michel AD et al (1998) Blockade of human P2X7 receptor function with a monoclonal anti body. Blood 92(10):3521–3528

    CAS  PubMed  Google Scholar 

  21. Denlinger LC, Fisette PL, Sommer JA et al (2001) Cutting edge: the nucleotide receptor P2X7 contains multiple protein- and lipid-interaction motifs including a potential binding site for bacterial lipopolysaccharide. J Immunol 167(4):1871–1876

    Article  CAS  PubMed  Google Scholar 

  22. Smart ML, Gu B, Panchal RG, Wiley J, Cromer B, Williams DA, Petrou S (2003) P2X7 receptor cell surface expression and cytolytic pore formation are regulated by a distal C-terminal region. J Biol Chem 278(10):8853–8860

    Article  CAS  PubMed  Google Scholar 

  23. Nicke A (2008) Homotrimeric complexes are the dominant assembly state of native P2X7 subunits. Biochem Bio phys Res Commun 19; 377(3):803–808

    Article  CAS  Google Scholar 

  24. Castrichini M, Lazzerini PE, Gamberucci A et al (2014) The purinergic P2 × 7 receptor is expressed on monocytes in Behçet’s disease and is modulated by TNF-α. Eur J Immunol 44(1):227–238

    Article  CAS  PubMed  Google Scholar 

  25. Collo G, Neidhart S, Kawashima E, Kosco-Vilbois M, North RA, Buell G (1997) Tissue distribution of the P2X7 receptor. Neuropharmacology 36(9):1277–1283

    Article  CAS  PubMed  Google Scholar 

  26. Deuchars SA, Atkinson L, Brooke RE et al (2001) Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems. J Neurosci 21(18):7143–7152

    CAS  PubMed  Google Scholar 

  27. Gartland A, Hipskind RA, Gallagher JA, Bowler WB (2001) Expression of a P2X7 receptor by a subpopulation of human osteoblasts. J Bone Miner Res 16(5):846–856

    Article  CAS  PubMed  Google Scholar 

  28. Gröschel-Stewart U, Bardini M, Robson T, Burnstock G (1999) Localization of P2X5 and P2X7 receptors by immunohistochemistry in rat stratified squamous epithelia. Cell Tissue Res 296(3):599–605

    Article  PubMed  Google Scholar 

  29. Solini A, Chiozzi P, Morelli A, Fellin R, Di Virgilio F (1999) Human primary fibroblasts in vitro express a purinergic P2X7 receptor coupled to ion fuxes, microvesicle formation and IL-6 release. J Cell Sci 112:297–305

    CAS  PubMed  Google Scholar 

  30. Caporali F, Capecchi PL, Gamberucci A et al (2008) Human rheumatoid synoviocytes express functional P2X7 receptors. J Mol Med 86(8):937–949

    Article  CAS  PubMed  Google Scholar 

  31. Arulkumaran N, Unwin RJ, Tam FW (2011) A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases. Expert Opin Investig Drugs 20(7):897–915

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Surprenant A, Rassendren F, Kawashima E, North RA, Buell G (1996) The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 272(5262):735–738

    Article  CAS  PubMed  Google Scholar 

  33. Di Virgilio F (1995) The P2z purino receptor: an intriguing role in immunity, inflammation and cell death. Immunol Today 16(11):524–528

    Article  PubMed  Google Scholar 

  34. Di Virgilio F, Falzoni S, Mutini C, Sanz JM, Chiozzi P (1998) Purinergic P2X7 receptor: a pivotal role in inflammation and immunomodulation. Drug Dev Res 145:207–213

    Article  Google Scholar 

  35. Lister MF, Sharkey J, Sawatzky DA, Hodgkiss JP, Davidson DJ, Rossi AG, Finlayson K (2007) The role of the purinergic P2X7 receptor in inflammation. J Inflamm (Lond) 16:4–5

    Google Scholar 

  36. Nathan C (2002) Points of control in inflammation. Nature 420(6917):846–852

    Article  CAS  PubMed  Google Scholar 

  37. Jounai N, Kobiyama K, Takeshita F, Ishii KJ (2013) Recognition of damage-associated molecular patterns related to nucleic acids during inflammation and vaccination. Front Cell Infect Microbiol 2:168

    Article  PubMed Central  PubMed  Google Scholar 

  38. Ferrari D, Chiozzi P, Falzoni S, Hanau S, Di Virgilio F (1997) Purinergic modulation of interleukin-1β release from microglial cells stimulated with bacterial endotoxin. J Exp Med 185(3):579–582

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Mariathasan S, Newton K, Monack DM, Vucic D et al (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430(6996):213–218

    Article  CAS  PubMed  Google Scholar 

  40. Rubartelli A, Lotze MT (2007) Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs). Trends Immunol 28(10):429–436

    Article  CAS  PubMed  Google Scholar 

  41. Sanz JM, Di Virgilio F (2000) Kinetics and mechanism of ATP-dependent IL-1β release from microglial cells. J Immunol 164(9):4893–4898

    Article  CAS  PubMed  Google Scholar 

  42. Mariathasan S, Monack DM (2007) Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7(1):31–40

    Article  CAS  PubMed  Google Scholar 

  43. LeRoy EC, Trojanowska MI, Smith EA (1990) Cytokines and human fibrosis. Eur Cytokine Netw 1(4):215–219

    CAS  PubMed  Google Scholar 

  44. Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214(2):199–210

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Eckes B, Zigrino P, Kessler D, Holtkotter O, Shephard P, Mauch C, Krieg T (2000) Fibroblast-matrix interactions in wound healing and fibrosis. Matrix Biol 19(4):325–332

    Article  CAS  PubMed  Google Scholar 

  46. Gabbiani G (2003) The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 200(4):500–503

    Article  CAS  PubMed  Google Scholar 

  47. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3(5):349–363

    Article  CAS  PubMed  Google Scholar 

  48. Postlethwaite AE, Raghow R, Stricklin GP, Poppleton H, Seyer JM, Kang AH (1998) Modulation of fibroblast functions by interleukin 1: increased steady-state accumulation of type I procollagen messenger RNAs and stimulation of other functions but not chemotaxis by human recombinant interleukin 1 alpha and beta. J Cell Biol 106(2):311–318

    Article  Google Scholar 

  49. Artlett CM (2012) The role of NLRP3 inflammasome in fibrosis. Open Rheumatol J 6:8086

    Article  Google Scholar 

  50. Gross TJ, Hunninghake GW (2001) Idiopathic pulmonary fibrosis. N Engl J Med 345(7):517–525

    Article  CAS  PubMed  Google Scholar 

  51. Chen Z, Jin N, Narasaraju T, Chen J, McFarland LR, Scott M, Liu L (2004) Identification of two novel markers for alveolar epithelial type I and II cells. Biochem Biophys Res Commun 319(3):774–780

    Article  CAS  PubMed  Google Scholar 

  52. Barth K, Kasper M (2009) Membrane compartments and purinergic signalling: occurrence and function of P2X receptors in lung. FEBS J 276(2):341–353

    Article  CAS  PubMed  Google Scholar 

  53. Belete HA, Hubmayr RD, Wang S, Singh RD (2011) The role of purinergic signaling on deformation induced injury and repair responses of alveolar epithelial cells. PLoS One 6(11), e27469

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Riteau N, Gasse P, Fauconnier L et al (2010) Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis. Am J Respir Crit Car Med 182(6):774–783

    Article  CAS  Google Scholar 

  55. Monção-Ribeiro LC, Faffe DS, Santana PT et al (2014) P2X7 receptor modulates inflammatory and functional pulmonary changes induced by silica. PLoS One 9(10):e110185

    Article  PubMed Central  PubMed  Google Scholar 

  56. Chen WC, Chen CC (1998) ATP-induced arachidonic acid release in cultured astrocytes is mediated by Gi protein coupled P2Y1 and P2Y2 receptors. Glia 22(4):360–370

    Article  CAS  PubMed  Google Scholar 

  57. Unwin RJ, Bailey MA, Burnstock G (2003) Purinergic signaling along the renal tubule: the current state of play. News Physiol Sci 18:237–241

    CAS  PubMed  Google Scholar 

  58. Bailey MA, Turner CM, Hus-Citharel A et al (2004) P2Y receptors present in the native and isolated rat glomerulus. Nephron Physiol 96(3):p79–p90

    Article  CAS  PubMed  Google Scholar 

  59. Shirley DG, Bailey MA, Unwin RJ (2005) In vivo stimulation of apical P2 receptors in collecting ducts: evidence for inhibition of sodium reabsorption. Am J Physiol 288:F1243–F1248

    CAS  Google Scholar 

  60. Vonend O, Turner CM, Chan CM et al (2004) Glomerular expression of the ATP-sensitive P2X receptor in diabetic and hypertensive rat models. Kidney Int 66(1):157–166

    Article  CAS  PubMed  Google Scholar 

  61. Solini A, Iacobini C, Ricci C et al (2005) Purinergic modulation of mesangial extracellular matrix production: role in diabetic and other glomerular diseases. Kidney Int 67(3):875–885

    Article  CAS  PubMed  Google Scholar 

  62. Gonçalves RG, Gabrich L, Rosário A Jr (2006) The role of purinergic P2X7 receptors in the inflammation and fibrosis of unilateral ureteral obstruction in mice. Kidney Int 70(9):1599–1606

    Article  PubMed  Google Scholar 

  63. Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115(2):209–218

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Benyon RC, Iredale JP (2000) Is liver fibrosis reversible? Gut 46(4):443–446

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Canbay A, Friedman S, Gores GJ (2004) Apoptosis: the nexus of liver injury and fibrosis. Hepatology 39(2):273–278

    Article  PubMed  Google Scholar 

  66. Li D, Friedman SL (1999) Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy. J Gastroenterol Hepatol 14(7):618–633

    Article  CAS  PubMed  Google Scholar 

  67. Casini A, Ceni E, Salzano R et al (1997) Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cell: role of nitric oxide. Hepatology 25(2):361–367

    Article  CAS  PubMed  Google Scholar 

  68. Viñas O, Bataller R, Sancho-Bru P et al (2003) Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte proliferation. Hepatology 38(4):919–929

    Article  PubMed  Google Scholar 

  69. Friedman SL (2003) Liver fibrosis—from bench to bedside. J Hepatol 38(Suppl 1):S38–S53

    Article  PubMed  Google Scholar 

  70. Bataller R, North KE, Brenner DA (2003) Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 37(3):493–503

    Article  CAS  PubMed  Google Scholar 

  71. Huang C, Yu W, Cui H, Wang Y, Zhang L, Han F, Huang T (2014) P2X7 blockade attenuates mouse liver fibrosis. Mol Med Rep 9(1):57–62

    CAS  PubMed  Google Scholar 

  72. Tung H-C, Lee F-Y, Wang S-S et al (2015) The beneficial effects of P2X7 antagonism in rats with bile duct ligation-induced cirrhosis. PLoS One 10(5):e0124654

    Article  PubMed Central  PubMed  Google Scholar 

  73. Burnstock G, Novak I (2012) Purinergic signalling in the pancreas in health and disease. J Endocrinol 213(2):123–141

    Article  CAS  PubMed  Google Scholar 

  74. Steer ML, Waxman I, Freedman S (1995) Chronic pancreatitis. N Engl J Med 332(22):1482–1490

    Article  CAS  PubMed  Google Scholar 

  75. Shimizu K (2008) Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis. J Gastroenterol 43(11):823–832

    Article  CAS  PubMed  Google Scholar 

  76. Apte MV, Haber PS, Darby SJ, Rodgers SC, McCaughan GW, Korsten MA et al (1999) Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut 44(4):534–541

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. McCarroll JA, Phillips PA, Kumar RK, Park S, Pirola RC, Wilson JS, Apte MV (2004) Pancreatic stellate cell migration: role of the phosphatidylinositol 3-kinase (PI3-kinase) pathway. Biochem Pharmacol 67:1215–1225

    Article  CAS  PubMed  Google Scholar 

  78. Bachem MG, Schneider E, Gross H, Adler G et al (1998) Identification, culture and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115(2):421–432

    Article  CAS  PubMed  Google Scholar 

  79. Haanes KA, Schwab A, Novak I (2012) The P2X7 receptor support both life and death in fibrogenic pancreatic stellate cells. PLoS One 7(12), e51164

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Künzli BM, Berberat PO, Giese T et al (2007) Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease. Am J Physiol Gastrointest Liver Physiol 292(1):G223–G230

    Article  PubMed  Google Scholar 

  81. Künzli BM, Nuhn P, Enjyoji K et al (2008) Disordered pancreatic inflammatory responses and inhibition of fibrosis in CD39-null mice. Gastroenterology 134(1):292–305

    Article  PubMed Central  PubMed  Google Scholar 

  82. Krenning G, Zeisberg EM, Kalluri R (2011) The origin of fibroblast and mechanism of cardiac fibrosis. J Cell Physiol 225(3):611–637

    Google Scholar 

  83. Weber KT (1997) Monitoring tissue repair and fibrosis from a distance. Circulation 96(8):2488–2492

    CAS  PubMed  Google Scholar 

  84. Gray MO, Long CS, Kalinyak JE, Li HT, Karliner JS (1998) Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-β1 and endothelin-1 from fibroblasts. Cardiovasc Res 40(2):352–363

    Article  CAS  PubMed  Google Scholar 

  85. Jiang ZS, Jeyaraman M, Wen GB, Fandrich RR, Dixon IMC, Cattini PA, Kardami E (2007) High- but not low-molecular weight FGF-2 causes cardiac hypertrophy in vivo; possible involvement of cardiotrophin-1. J Mol Cell Cardiol 42(1):222–233

    Article  CAS  PubMed  Google Scholar 

  86. Mezzaroma E, Toldo S, Farkas D et al (2011) The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci U S A 108(49):19725–19730

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Sandanger Ø, Ranheim T, Vinge LE et al (2013) The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia–reperfusion injury. Cardiovasc Res 99(1):164–174

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Viale Bracci 16, Siena, 53100, Italy

    Daniela Gentile, Mariarita Natale, Pietro Enea Lazzerini, Pier Leopoldo Capecchi & Franco Laghi-Pasini

Authors
  1. Daniela Gentile
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariarita Natale
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pietro Enea Lazzerini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pier Leopoldo Capecchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Franco Laghi-Pasini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniela Gentile.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gentile, D., Natale, M., Lazzerini, P.E. et al. The role of P2X7 receptors in tissue fibrosis: a brief review. Purinergic Signalling 11, 435–440 (2015). https://doi.org/10.1007/s11302-015-9466-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11302-015-9466-3

Keywords

Search

Navigation