The platelet P2 receptors in inflammation

M. Cattaneo

doi:10.5482/HAMO-14-09-0044

Hämostaseologie, Table of Contents

Hamostaseologie 2015; 35(03): 262-266
DOI: 10.5482/HAMO-14-09-0044

Review

Schattauer GmbH

The platelet P2 receptors in inflammation

Der Plättchen-P2-Rezeptor bei Entzündungen

Authors

M. Cattaneo

¹Divisione di Medicina Generale III, Azienda Ospedaliera San Paolo, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Italy

Abstract

Summary

In addition to their well characterized and established role in haemostasis and thrombosis, platelets contribute to the pathogenesis of inflammation. Adenine nucleotides are signalling molecules that regulate the function of virtually every cell in the body, by interacting with P2 receptors. Their important role in inflammation is well established. In the last few years, the pro-inflammatory roles of adenine nucleotides interacting with their platelet P2 receptors has emerged. In particular, it was shown that the platelet P2Y₁₂ receptor for ADP significantly contributed to the proinflammatory effects of cysteinyl leukotrienes (CysLT) in experimental models of asthma in mice. More importantly, it was recently shown that P2Y₁₂ variants were associated with lung function in a large family-based asthma cohort and that the P2Y₁₂ antagonist prasugrel tended to decrease bronchial hyper-reactivity to mannitol in patients with allergic bronchial asthma in a randomized, placebo controlled trial.

Conclusion

These data strongly suggest that P2Y₁₂ may represent an important pharmacological target for the treatment of patients with allergic bronchial asthma.

Zusammenfassung

Neben ihrer gut beschriebenen und etablierten Rolle bei Hämostase und Thrombose tragen die Thrombozyten auch zur Pathogenese von Entzündungen bei. Adenin-Nukleotide sind Signalmoleküle, die über die Interaktion mit P2-Rezeptoren die Funktion praktisch aller Körperzellen regulieren. Ihre wichtige Rolle bei Entzündungen ist gut belegt. In den letzten Jahren wurden die pro-inflammatorischen Wirkungen für Adenin-Nukleotide, die mit Plättchen-P2-Rezeptoren interagieren, beschrieben. Insbesondere wurde gezeigt, dass der Plättchen-P2Y₁₂-Rezeptor für ADP in experimentellen Asthmamodellen bei Mäusen maßgeblich zu den pro-inflammatorischen Wirkungen der Cysteinyl-Leukotriene (CysLT) beiträgt. Darüber hinaus wurde kürzlich nachgewiesen, dass P2Y₁₂-Varianten in einer großen, familienbasierten Asthma-Kohorte mit der Lungenfunktion assoziiert waren und dass der P2Y₁₂-Antagonist Prasugrel in einer randomisierten, Placebo-kontrollierten Studie die bronchiale Hyperreaktivität gegen Mannitol bei Patienten mit allergischem Bronchialasthma tendenziell verringerte.

Schlussfolgerung

Diese Daten liefern starke Anhaltspunkte dafür, dass P2Y₁₂ ein wichtiges pharmakologisches Ziel für die Behandlung von Patienten mit allergischem Bronchialasthma darstellen könnte.

Keywords

P2Y12 - asthma - inflammation - platelets - cysteinyl leukotriens

Schlüsselwörter

P2Y12 - Asthma - Entzündung - Plättchen - Cysteinyl-Leukotriene

Full Text

References

References
1 Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11: 264-274.
2 Amison R, Page C, Pitchford S. Pharmacological modulation of the inflammatory actions of platelets. Handb Exp Pharmacol. 2012: 447-468.
3 Ware J, Corken A, Khetpal R. Platelet function beyond hemostasis and thrombosis. Curr Opin Hematol 2013; 20: 451-456.
4 Morrell CN, Aggrey AA, Chapman LM, Modjeski KL. Emerging roles for platelets as immune and inflammatory cells. Blood 2014; 123: 2759-2767.
5 Erpenbeck L, Schön MP. Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood 2010; 115: 3427-3436.
6 Müller F, Mutch NJ, Schenk WA. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139: 1143-1156.
7 Shi G, Field DJ, Ko KA. et al. Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection. J Clin Invest 2014; 124: 543-552.
8 Von Hundelshausen P, Weber KS, Huo Y. et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 2001; 103: 1772-1777.
9 Boilard E, Nigrovic PA, Larabee K. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327: 580-583.
10 Zimmerman GA, Weyrich AS. Immunology. Arsonists in rheumatoid arthritis. Science 2010; 327: 528-529.
11 Langer HF, Choi EY, Zhou H. et al. Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis. Circ Res 2012; 110: 1202-1210.
12 Totani L, Evangelista V. Platelet-leukocyte interactions in cardiovascular disease and beyond. Arterioscler Thromb Vasc Biol 2010; 30: 2357-2361.
13 Fuentes QE, Fuentes QF, Andres V. et al. Role of platelets as mediators that link inflammation and thrombosis in atherosclerosis. Platelets 2012; 24: 255-262.
14 Li N. CD4+ T cells in atherosclerosis: Regulation by platelets. Thromb Haemost 2013; 109: 980-990.
15 Caudrillier A, Looney MR. Platelet-neutrophil interactions as a target for prevention and treatment of transfusion-related acute lung injury. Curr Pharm Des 2012; 18: 3260-3266.
16 Boilard E, Blanco P, Nigrovic PA. Platelets: active players in the pathogenesis of arthritis and SLE. Nat Rev Rheumatol 2012; 08: 534-542.
17 Knauer KA, Fish JE, Adkinson Jr NF. et al. Platelet activation in antigen-induced bronchoconstriction. N Engl J Med 1981; 305: 892-893.
18 Pitchford SC, Yano H, Lever R. et al. Platelets are essential for leukocyte recruitment in allergic inflammation. J Allergy Clin Immunol 2003; 112: 109-118.
19 Pitchford SC, Riffo-Vasquez Y, Sousa A. et al. Platelets are necessary for airway wall remodeling in a murine model of chronic allergic inflammation. Blood 2004; 103: 639-647.
20 Pitchford SC, Momi S, Baglioni S. et al. Allergen induces the migration of platelets to lung tissue in allergic asthma. Am J Respir Crit Care Med 2008; 177: 604-612.
21 Cattaneo M. The platelet P2 receptors. In: Michelson AD. (ed). Platelets. Philadelphia: Academic Press; 2013: 261-282.
22 Idzko M, Ferrari D, Eltzschig HK. Nucleotide signalling during inflammation. Nature 2014; 509: 310-317.
23 Zerr M, Hechler B, Freund M. et al. Major contribution of the P2Y₁receptor in purinergic regulation of TNFα-induced vascular inflammation. Circulation 2011; 123: 2404-2413.
24 Künzli BM, Berberat PO, Giese T. et al. Upregulation of CD39/NTPDases and P2receptors in human pancreatic disease. Am J Physiol Gastrointest Liver Physiol 2007; 292: G223-G230.
25 Lommatzsch M, Cicko S, Müller T. et al. Extracellular adenosine triphosphate and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010; 181: 928-934.
26 Cicko S, Lucattelli M, Müller T. et al. Purinergic receptor inhibition prevents the development of smoke-induced lung injury and emphysema. J Immunol 2010; 185: 688-697.
27 Vanderstocken G, Bondue B, Horckmans M. et al. P2Y2 receptor regulates VCAM-1 membrane and soluble forms and eosinophil accumulation during lung inflammation. J Immunol 2010; 185: 3702-3707.
28 Younas M, Hue S, Lacabaratz C, Guguin A. et al. IL-7 modulates in vitro and in vivo human memory T regulatory cell functions through the CD39/ATP axis. J Immunol 2013; 191: 3161-3168.
29 Zimmermann H, Zebisch M, Strater N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 2012; 08: 437-502.
30 Müller T, Vieira RP, Grimm M. et al. A potential role for P2X7R in allergic airway inflammation in mice and humans. Am J Respir Cell Mol Biol 2011; 44: 456-464.
31 Manthei DM, Jackson DJ, Evans MD. et al. Protection from asthma in a high-risk birth cohort by attenuated P2X(7) function. J Allergy Clin Immunol 2012; 130: 496-502.
32 Gulbransen BD, Bashashati M, Hirota SA. et al. Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nat Med 2012; 18: 600-604.
33 Kurashima Y, Amiya T, Nochi T. et al. Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors. Nat Commun 2012; 03: 1034.
34 Köhler D, Eckle T, Faigle M. et al. CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury. Circulation 2007; 116: 1784-1794.
35 Pinsky DJ, Broekman MJ, Peschon JJ. et al. Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain. J Clin Invest 2002; 109: 1031-1040.
36 Marcus AJ, Safier LB, Hajjar KA. et al. Inhibition of platelet function by an aspirin-insensitive endothelial cell ADPase. Thromboregulation by endothelial cells. J Clin Invest 1991; 88: 1690-1696.
37 Hyman MC, Petrovic-Djergovic D, Visovatti SH. et al. Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39. J Clin Invest 2009; 119: 1136-1149.
38 Eltzschig HK, Sitkovsky MV, Robson SC. Purinergic signaling during inflammation. N Engl J Med 2012; 367: 2322-2333.
39 Cattaneo M, Schulz R, Nylander S. Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance. J Am Coll Cardiol 2014; 63: 2503-2509.
40 Barletta KE, Ley K, Mehrad B. Regulation of neutrophil function by adenosine. Arterioscler Thromb Vasc Biol 2012; 32: 856-864.
41 Csóka B, Németh ZH, Rosenberger P. et al. A2B adenosine receptors protect against sepsis-induced mortality by dampening excessive inflammation. J Immunol 2010; 185: 542-550.
42 Ohta A, Sitkovsky M. Role of G-protein-coupled adenosine receptors indownregulation of inflammation and protection from tissue damage. Nature 2001; 414: 916-920.
43 Friedman DJ, Künzli BM, A-Rahim YI. et al. CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease. Proc Natl Acad Sci USA 2009; 106: 16788-16793.
44 Eckle T, Füllbier L, Wehrmann M. et al. Identification of ectonucleotidases CD39 and CD73 in innate protection during acute lung injury. J Immunol 2007; 178: 8127-37.
45 Léon C, Ravanat C, Freund M. et al. Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity. Arterioscler Thromb Vasc Biol 2003; 23: 1941-1947.
46 Hermann A, Rauch BH, Braun M. et al. Platelet CD40 ligand subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets 2001; 12: 74-82.
47 Cattaneo M. ADP receptor antagonists. In: Michelson AD. (ed). Platelets. Philadelphia: Academic Press; 2013: 1117-1139.
48 Liu O, Jia L, Liu X. et al. Clopidogrel, a platelet P2Y12 receptor inhibitor, reduces vascular inflammation and angiotensin II induced-abdominal aortic aneurysm progression. PLoS One 2012; 07: e51707.
49 Vivekananthan DP, Bhatt DL, Chew DP. et al. Effect of clopidogrel pretreatment on periprocedural rise in C-reactive protein after percutaneous coronary intervention. Am J Cardiol 2004; 94: 358-360.
50 Steinhubl SR, Badimon JJ, Bhatt DL. et al. Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med 2007; 12: 113-122.
51 Patti G, Grieco D, Dicuonzo G. et al. High versus standard clopidogrel maintenance dose after percutaneous coronary intervention and effects on platelet inhibition, endothelial function, and inflammation results of the ARMYDA-150 mg randomized study. J Am Coll Cardiol 2011; 57: 771-778.
52 Waehre T, Damås JK, Pedersen TM. et al. Clopidogrel increases expression of chemokines in peripheral blood mononuclear cells in patients with coronary artery disease: results of a double-blind placebo-controlled study. J Thromb Haemost 2006; 04: 2140-2147.
53 Aukrust P. Clopidogrel increases expression of chemokines in peripheral blood mononuclear cells in patients with coronary artery disease: Results of a double-blind placebo-controlled study. J. Thromb Haemost 2006; 04: 2140-2147.
54 Palmerini T, Barozzi C, Tomasi L. et al. A randomised study comparing the antiplatelet and anti-inflammatory effect of clopidogrel 150 mg/day versus 75 mg/day in patients with ST-segment elevation acute myocardial infarction and poor responsiveness to clopidogrel: results from the DOUBLE study. Thromb Res 2010; 125: 309-314.
55 Ostad MA, Nick E, Paixao-Gatinho V. et al. Lack of evidence for pleiotropic effects of clopidogrel on endothelial function and inflammation in patients with stable coronary artery disease: results of the double-blind, randomized CASSANDRA study. Clin Res Cardiol 2011; 100: 29-36.
56 Husted S, Storey RF, Harrington RA. et al. Changes in inflammatory biomarkers in patients treated with ticagrelor or clopidogrel. Clin Cardiol 2010; 33: 206-212.
57 Woodward M, Lowe GD, Francis LM. et al. A randomized comparison of the effects of aspirin and clopidogrel on thrombotic risk factors and C-reactive protein following myocardial infarction: The CADET trial. J Thromb Haemost 2004; 02: 1934-1940.
58 Muhlestein JB. Effect of antiplatelet therapy on inflammatory markers in atherothrombotic patients. Thromb Haemost 2010; 103: 71-82.
59 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes 2006; 55: 780-784.
60 Wihlborg AK, Wang L, Braun OO. et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol 2004; 24: 1810-1815.
61 Rauch BH, Rosenkranz AC, Ermler S. et al. Regulation of functionally active P2Y12 ADP receptors by thrombin in human smooth muscle cells and the presence of P2Y12 in carotid artery lesions. Arterioscler Thromb Vasc Biol 2010; 30: 2434-2442.
62 Laidlaw TM, Boyce JA. Cysteinyl leukotriene receptors, old and new; implications for asthma. Clin Exp Allergy 2012; 42: 1313-1320.
63 Samuelsson B, Dahlen SE, Lindgren JA. et al. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 1987; 237: 1171-1176.
64 Hui Y, Yang G, Galczenski H, Figueroa DJ. et al. The murine cysteinyl leukotriene 2 receptor. cDNA and genomic cloning, alternative splicing, and in vitro characterization. J Biol Chem 2001; 276: 47489-47495.
65 Heise CE, O’Dowd BF, Figueroa DJ. et al. Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem 2000; 275: 30531-30536.
66 Kanaoka Y, Maekawa A, Austen KF. Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand. J Biol Chem 2013; 288: 10967-10972.
67 Hasegawa S, Ichiyama T, Hashimoto K. et al. Functional expression of cysteinyl leukotriene receptors on human platelets. Platelets 2010; 21: 253-259.
68 Cattaneo M. New P2Y(12) inhibitors. Circulation 2010; 121: 171-179.
69 Paruchuri S, Tashimo H, Feng C. et al. Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor. J Exp Med 2009; 206: 2543-2555.
70 Cummings HE, Liu T, Feng C. et al. Cutting edge: Leukotriene C4 activates mouse platelets in plasma exclusively through the type 2 cysteinyl leukotriene receptor. J Immunol 2013; 191: 5807-5810.
71 Nonaka Y, Hiramoto T, Fujita N. Identification of endogenous surrogate ligands for human P2Y12 receptors by in silico and in vitro methods. Biochem Biophys Res Commun 2005; 337: 281-288.
72 Bunyavanich S, Boyce JA, Raby BA, Weiss ST. Gene-by-environment effect of house dust mite on purinergic receptor P2Y12 (P2RY12) and lung function in children with asthma. Clin Exp Allergy 2012; 42: 229-237.
73 Lussana F, Di Marco F, Terraneo S. et al. Effect of prasugrel in patients with asthma: sresults of PRINA, a randomized, double-blind, placebo-controlled, cross-over study. J Thromb Haemost. 2014 doi: 10.1111/jth.12779.
74 Joos GF, O’Connor B, Anderson SD. et al. Indirect airway challenges. Eur Respir J 2003; 21: 1050-1068.
75 Leuppi JD, Brannan JD, Anderson SD. Bronchial provocation tests: the rationale for using inhaled mannitol as a test for airway hyperresponsiveness. Swiss Med Wkly 2002; 132: 151-158.
76 Cattaneo M, Faioni EM. Why does ticagrelor induce dyspnea?. Thromb Haemost 2012; 108: 1031-1036.