P2X7受体与炎症相关性疾病
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摘要
P2X7是一种在多种免疫细胞中广泛表达的以ATP为配体的阳离子通道受体,它的激活能引起和加重炎症反应。当细胞处于损伤、缺氧或炎症状态时, P2X7受体可被释放到胞外的大量ATP激活,进而通过活化NLRP3炎症小体、调节基因转录等方式,影响炎症介质(IL-1β、IL-18等)的释放从而参与多种炎症性疾病,如糖尿病肾病、系统性红斑狼疮(systemic lupus erythematosus,SLE)等。近年来,细胞外ATP-P2X7受体信号通路已成为炎症性疾病研究较多的通路之一。大量研究表明, P2X7受体是治疗炎症性疾病的潜在靶点。该文将对P2X7受体及其参与的炎症相关性疾病的关系作一综述。
The P2 X7 is a ATP-gated cationic channel receptor and widely expressed in a variety of immune cells, where its activation triggers and aggravates the inflammatory reaction. When cells are damaged, hypoxic or inflammatory, large-scale ATP is released into the extracellular matrix, then activates P2 X7 receptor. Activated P2 X7 receptor induces the release of inflammatory cytokines(IL-1β, IL-18, etc.) by mediating the activation of NLRP3 inflammasome and regulating gene transcription, etc, thus participating in various inflammatory diseases,such as diabetic nephropathy, systemic lupus erythematosus and so on. In recent years, extracellular ATP-P2 X7 receptor signaling pathway has become one of the most popular pathways in inflammatory diseases. Many studies have shown that the P2 X7 receptor is a potential target to treat inflammatory diseases. In this review, we discuss the relationship between P2 X7 receptor and inflammatory related diseases.
The P2 X7 is a ATP-gated cationic channel receptor and widely expressed in a variety of immune cells, where its activation triggers and aggravates the inflammatory reaction. When cells are damaged, hypoxic or inflammatory, large-scale ATP is released into the extracellular matrix, then activates P2 X7 receptor. Activated P2 X7 receptor induces the release of inflammatory cytokines(IL-1β, IL-18, etc.) by mediating the activation of NLRP3 inflammasome and regulating gene transcription, etc, thus participating in various inflammatory diseases,such as diabetic nephropathy, systemic lupus erythematosus and so on. In recent years, extracellular ATP-P2 X7 receptor signaling pathway has become one of the most popular pathways in inflammatory diseases. Many studies have shown that the P2 X7 receptor is a potential target to treat inflammatory diseases. In this review, we discuss the relationship between P2 X7 receptor and inflammatory related diseases.
引文
1 Jones S,Evans RJ,Mahaut-Smith MP.Ca2+influx through P2X1receptors amplifies P2Y1 receptor-evoked Ca2+signaling and mADP-evoked platelet aggregation.Mol Pharmacol 2014;86(3):243-51.
2徐宏,梁尚栋.P2X7受体在炎症性疾病中的作用及其机制.生理学报(Xu Hong,Liang Shangdong.Effect of P2X7 receptor on inflammatory diseases and its mechanism.Acta Physiologica Sinica)2013;65(2):244-52.
3 Wang XH,Xie X,Luo XG,Shang H,He ZY.Inhibiting purinergic P2X7 receptors with the antagonist brilliant blue G is neuroprotective in an intranigral lipopolysaccharide animal model of Parkinson’s disease.Mol Med Rep 2017;15(2):768-76.
4 Zhao J,Wang H,Dai C,Wang H,Zhang H,Huang Y,et al.P2X7blockade attenuates murine lupus nephritis by inhibiting activation of the NLRP3/ASC/caspase 1 pathway.Arthritis Rheum2013;65(12):3176-85.
5 Solini A,Menini S,Rossi C,Ricci C,Santini E,Blasetti Fantauzzi C,et al.The purinergic 2X7 receptor participates in renal inflammation and injury induced by high-fat diet:possible role of NLRP3 inflammasome activation.J Pathol 2013;231(3):342-53.
6杨艳,张玉秋.P2X7受体在病理性疼痛中的研究进展.中国细胞生物学学报(Yang Yan,Zhang Yuqiu.Progress of P2X7 receptor research in chronic pain.Chinese Journal of Cell Biology)2014;36(5):561-9.
7习德娥,韩莉,谭超,杨晓东.P2X7受体与基因转录的关系.中国免疫学杂志(Xi Dee,Han Li,Tan Chao,Yang Xiaodong.Relationship between P2X7 receptor and gene transcription.Chinese Journal of Immunology)2015;31(9):1294-7.
8习德娥,韩莉,卢建明.P2X7受体与炎性细胞因子.中国真菌学杂志(Xi Dee,Han Li,Lu Jianming.P2X7 receptor and inflammation cytokine.Chinese Journal of Mycology)2014;9(4):252-6.
9 Hechler B,Gachet C.Purinergic receptors in thrombosis and inflammation.Arterioscler Thromb Vasc Biol 2015;35(11):2307-15.
10 Karmakar M,Katsnelson MA,Dubyak GR,Pearlman E.Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1βsecretion in response to ATP.Nat Commun 2016;7:10555.
11 He Y,Franchi L,Nú?ez G.TLR agonists stimulate Nlrp3-dependent IL-1βproduction independently of the purinergic P2X7receptor in dendritic cells and in vivo.J Immunol 2013;190(1):334-9.
12 Di A,Xiong S,Ye Z,Malireddi RKS,Kometani S,Zhong M,et al.The TWIK2 potassium efflux channel in macrophages mediates NLRP3 inflammasome-induced inflammation.Immunity2018;49(1):56-65.
13李瑞,郭玉娟,范晴晴,颜天华.NF-κB信号通路在肾间质纤维化发展的作用研究.药学与临床研究(Li Rui,Guo Yujuan,Fan Qingqing,Yan Tianhua.Role of NF-κB signaling in the development of renal interstitial fibrosis.Pharmaceutical and Clinical Research)2018;26(1):43-8.
14 Ma B,Hottiger MO.Crosstalk between Wnt/β-Catenin and NF-κBsignaling pathway during inflammation.Front Immunol 2016;7:378.
15 Espín-Palazón R,Traver D.The NF-κB family:Key players during embryonic development and HSC emergence.Exp Hematol2016;44(7):519-27.
16 Taefehshokr S,Key YA,Khakpour M,Dadebighlu P,Oveisi A.Early growth response 2 and Egr3 are unique regulators in immune system.Cent Eur J Immunol 2017;42(2):205-9.
17 Friedle SA,Brautigam VM,Nikodemova M,Wright ML,Watters JJ.The P2X7-Egr pathway regulates nucleotide-dependent inflammatory gene expression in microglia.Glia 2011;59(1):1-13.
18 Gazon H,Barbeau B,Mesnard JM,Peloponese JM Jr.Hijacking of the AP-1 Signaling Pathway during Development of ATL.Front Microbiol 2018;8:2686.
19 Gavala ML,Hill LM,Lenertz LY,Karta MR,Bertics PJ.Activation of the transcription factor FosB/activating protein-1(AP-1)is a prominent downstream signal of the extracellular nucleotide receptor P2RX7 in monocytic and osteoblastic cells.J Biol Chem2010;285(44):34288-98.
20 Alshammari EM,Mandal RK,Wahid M,Dar SA,Jawed A,Areeshi MY,et al.Genetic association study of P2x7 A1513C(rs3751143)polymorphism and susceptibility to pulmonary tuberculosis:A meta-analysis based on the findings of 11 case-control studies.Asian Pac J Trop Med 2016;9(12):1150-7.
21 Fernando SL,Saunders BM,Sluyter R,Skarratt KK,Goldberg H,Marks GB,et al.A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis.Am J Respir Crit Care Med 2007;175(4):360-6.
22 Haas SL,Ruether A,Singer MV,Schreiber S,B?cker U.Functional P2X7 receptor polymorphisms(His155Tyr,Arg307Gln,Glu496Ala)in patients with Crohn’s disease.Scand J Immunol2007;65(2):166-70.
23 Portales-Cervantes L,Ni?o-Moreno P,Salgado-Bustamante M,García-Hernández MH,Baranda-Candido L,Reynaga-Hernández E,et al.The His155Tyr(489C>T)single nucleotide polymorphism of P2RX7 gene confers an enhanced function of P2X7receptor in immune cells from patients with rheumatoid arthritis.Cell Immunol 2012;276(1-2):168-75.
24 Stokes L,Fuller SJ,Sluyter R,Skarratt KK,Gu BJ,Wiley JS.Two haplotypes of the P2X(7)receptor containing the Ala-348 to Thr polymorphism exhibit a gain-of-function effect and enhanced interleukin-1beta secretion.FASEB J 2010;24(8):2916-27.
25 Monif M,Reid CA,Powell KL,Smart ML,Williams DA.The P2X7 receptor drives microglial activation and proliferation:a trophic role for P2X7R pore.J Neurosci 2009;29(12):3781-91.
26 Kaiser M,Penk A,Franke H,Krügel U,N?renberg W,Huster D,et al.Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion.Purinergic Signal 2016;12(3):453-63.
27 Caglayan B,Caglayan AB,Beker MC,Yalcin E,Beker M,Kelestemur T,et al.Evidence that activation of P2X7R does not exacerbate neuronal death after optic nerve transection and focal cerebral ischemia in mice.Exp Neurol 2017;296:23-31.
28 Grygorowicz T,Stru?yńska L.Early P2X7R-dependent activation of microglia during the asymptomatic phase of autoimmune encephalomyelitis.Inflammopharmacology 2019;27(1):129-37.
29 Martin E,Amar M,Dalle C,Youssef I,Boucher C,Le Duigou C,et al.New role of P2X7 receptor in an Alzheimer’s disease mouse model.Mol Psychiatry 2019;24(1):108-25.
30 McInnes IB,Cruwys S,Bowers K,Braddock M.Targeting the P2X7 receptor in rheumatoid arthritis:biological rationale for P2X7 antagonism.Clin Exp Rheumatol 2014;32(6):878-82.
31 Baldini C,Rossi C,Ferro F,Santini E,Seccia V,Donati V,et al.The P2X7 receptor-inflammasome complex has a role in modulating the inflammatory response in primary Sj?gren’s syndrome.J Intern Med 2013;274(5):480-9.
32 Khalafalla MG,Woods LT,Camden JM,Khan AA,Limesand KH,Petris MJ,et al.P2X7 receptor antagonism prevents IL-1βrelease from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy.J Biol Chem2017;292(40):16626-37.
33马秀英,张源明,戴晨,王梦如,郭小亚,董建.P2X7受体在肾脏相关疾病中作用的研究进展.医学综述(Ma Xiuying,Zhang Yuanming,Dai Chen,Wang Mengru,Guo Xiaoya,Dong Jian.Research progress of P2X7 receptor in kidney related diseases.Medical Recapitulate)2017;23(20):3963-7.
34 Rodrigues AM,Bergamaschi CT,Fernandes MJ,Paredes-Gamero EJ,Buri MV,Ferreira AT,et al.P2X(7)receptor in the kidneys of diabetic rats submitted to aerobic training or to N-acetylcysteine supplementation[corrected].PLoS One 2014;9(6):e97452.
35 Menzies RI,Booth JWR,Mullins JJ,Bailey MA,Tam FWK,Norman JT,et al.Hyperglycemia-induced Renal P2X7 Receptor Activation Enhances Diabetes-related Injury.EbioMedicine2017;19:73-83.
36 Yan Y,Bai J,Zhou X,Tang J,Jiang C,Tolbert E,et al.P2X7receptor inhibition protects against ischemic acute kidney injury in mice.Am J Physiol Cell Physiol 2015;308(6):C463-72.
37 Franco M,Bautista-Pérez R,Cano-Martínez A,Pacheco U,Santamaría J,Del Valle Mondragón L,et al.Physiopathological implications of P2X(1)and P2X(7)receptors in regulation of glomerular hemodynamics in angiotensin II-induced hypertension.Am J Physiol Renal Physiol 2017;313(1):F9-19.
38 Müller T,Vieira RP,Grimm M,Dürk T,Cicko S,Zeiser R,et al.A potential role for P2X7R in allergic airway inflammation in mice and humans.Am J Respir Cell Mol Biol 2011;44(4):456-64.
39 Li R,Wang J,Li R,Zhu F,Xu W,Zha G,et al.ATP/P2X7-NLRP3 axis of dendritic cells participates in the regulation of airway inflammation and hyper-responsiveness in asthma by mediating HMGB1 expression and secretion.Exp Cell Res 2018;366(1):1-15.
40 Mon??o-Ribeiro LC,Faffe DS,Santana PT,Vieira FS,da Gra?a CL,Marques-da-Silva C,et al.P2X7 receptor modulates inflammatory and functional pulmonary changes induced by silica.PLoS One 2014;9(10):e110185.
41 Wang S,Zhao J,Wang H,Liang Y,Yang N,Huang Y.Blockage of P2X7 attenuates acute lung injury in mice by inhibiting NLRP3inflammasome.Int Immunopharmacol 2015;27(1):38-45.
2徐宏,梁尚栋.P2X7受体在炎症性疾病中的作用及其机制.生理学报(Xu Hong,Liang Shangdong.Effect of P2X7 receptor on inflammatory diseases and its mechanism.Acta Physiologica Sinica)2013;65(2):244-52.
3 Wang XH,Xie X,Luo XG,Shang H,He ZY.Inhibiting purinergic P2X7 receptors with the antagonist brilliant blue G is neuroprotective in an intranigral lipopolysaccharide animal model of Parkinson’s disease.Mol Med Rep 2017;15(2):768-76.
4 Zhao J,Wang H,Dai C,Wang H,Zhang H,Huang Y,et al.P2X7blockade attenuates murine lupus nephritis by inhibiting activation of the NLRP3/ASC/caspase 1 pathway.Arthritis Rheum2013;65(12):3176-85.
5 Solini A,Menini S,Rossi C,Ricci C,Santini E,Blasetti Fantauzzi C,et al.The purinergic 2X7 receptor participates in renal inflammation and injury induced by high-fat diet:possible role of NLRP3 inflammasome activation.J Pathol 2013;231(3):342-53.
6杨艳,张玉秋.P2X7受体在病理性疼痛中的研究进展.中国细胞生物学学报(Yang Yan,Zhang Yuqiu.Progress of P2X7 receptor research in chronic pain.Chinese Journal of Cell Biology)2014;36(5):561-9.
7习德娥,韩莉,谭超,杨晓东.P2X7受体与基因转录的关系.中国免疫学杂志(Xi Dee,Han Li,Tan Chao,Yang Xiaodong.Relationship between P2X7 receptor and gene transcription.Chinese Journal of Immunology)2015;31(9):1294-7.
8习德娥,韩莉,卢建明.P2X7受体与炎性细胞因子.中国真菌学杂志(Xi Dee,Han Li,Lu Jianming.P2X7 receptor and inflammation cytokine.Chinese Journal of Mycology)2014;9(4):252-6.
9 Hechler B,Gachet C.Purinergic receptors in thrombosis and inflammation.Arterioscler Thromb Vasc Biol 2015;35(11):2307-15.
10 Karmakar M,Katsnelson MA,Dubyak GR,Pearlman E.Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1βsecretion in response to ATP.Nat Commun 2016;7:10555.
11 He Y,Franchi L,Nú?ez G.TLR agonists stimulate Nlrp3-dependent IL-1βproduction independently of the purinergic P2X7receptor in dendritic cells and in vivo.J Immunol 2013;190(1):334-9.
12 Di A,Xiong S,Ye Z,Malireddi RKS,Kometani S,Zhong M,et al.The TWIK2 potassium efflux channel in macrophages mediates NLRP3 inflammasome-induced inflammation.Immunity2018;49(1):56-65.
13李瑞,郭玉娟,范晴晴,颜天华.NF-κB信号通路在肾间质纤维化发展的作用研究.药学与临床研究(Li Rui,Guo Yujuan,Fan Qingqing,Yan Tianhua.Role of NF-κB signaling in the development of renal interstitial fibrosis.Pharmaceutical and Clinical Research)2018;26(1):43-8.
14 Ma B,Hottiger MO.Crosstalk between Wnt/β-Catenin and NF-κBsignaling pathway during inflammation.Front Immunol 2016;7:378.
15 Espín-Palazón R,Traver D.The NF-κB family:Key players during embryonic development and HSC emergence.Exp Hematol2016;44(7):519-27.
16 Taefehshokr S,Key YA,Khakpour M,Dadebighlu P,Oveisi A.Early growth response 2 and Egr3 are unique regulators in immune system.Cent Eur J Immunol 2017;42(2):205-9.
17 Friedle SA,Brautigam VM,Nikodemova M,Wright ML,Watters JJ.The P2X7-Egr pathway regulates nucleotide-dependent inflammatory gene expression in microglia.Glia 2011;59(1):1-13.
18 Gazon H,Barbeau B,Mesnard JM,Peloponese JM Jr.Hijacking of the AP-1 Signaling Pathway during Development of ATL.Front Microbiol 2018;8:2686.
19 Gavala ML,Hill LM,Lenertz LY,Karta MR,Bertics PJ.Activation of the transcription factor FosB/activating protein-1(AP-1)is a prominent downstream signal of the extracellular nucleotide receptor P2RX7 in monocytic and osteoblastic cells.J Biol Chem2010;285(44):34288-98.
20 Alshammari EM,Mandal RK,Wahid M,Dar SA,Jawed A,Areeshi MY,et al.Genetic association study of P2x7 A1513C(rs3751143)polymorphism and susceptibility to pulmonary tuberculosis:A meta-analysis based on the findings of 11 case-control studies.Asian Pac J Trop Med 2016;9(12):1150-7.
21 Fernando SL,Saunders BM,Sluyter R,Skarratt KK,Goldberg H,Marks GB,et al.A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis.Am J Respir Crit Care Med 2007;175(4):360-6.
22 Haas SL,Ruether A,Singer MV,Schreiber S,B?cker U.Functional P2X7 receptor polymorphisms(His155Tyr,Arg307Gln,Glu496Ala)in patients with Crohn’s disease.Scand J Immunol2007;65(2):166-70.
23 Portales-Cervantes L,Ni?o-Moreno P,Salgado-Bustamante M,García-Hernández MH,Baranda-Candido L,Reynaga-Hernández E,et al.The His155Tyr(489C>T)single nucleotide polymorphism of P2RX7 gene confers an enhanced function of P2X7receptor in immune cells from patients with rheumatoid arthritis.Cell Immunol 2012;276(1-2):168-75.
24 Stokes L,Fuller SJ,Sluyter R,Skarratt KK,Gu BJ,Wiley JS.Two haplotypes of the P2X(7)receptor containing the Ala-348 to Thr polymorphism exhibit a gain-of-function effect and enhanced interleukin-1beta secretion.FASEB J 2010;24(8):2916-27.
25 Monif M,Reid CA,Powell KL,Smart ML,Williams DA.The P2X7 receptor drives microglial activation and proliferation:a trophic role for P2X7R pore.J Neurosci 2009;29(12):3781-91.
26 Kaiser M,Penk A,Franke H,Krügel U,N?renberg W,Huster D,et al.Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion.Purinergic Signal 2016;12(3):453-63.
27 Caglayan B,Caglayan AB,Beker MC,Yalcin E,Beker M,Kelestemur T,et al.Evidence that activation of P2X7R does not exacerbate neuronal death after optic nerve transection and focal cerebral ischemia in mice.Exp Neurol 2017;296:23-31.
28 Grygorowicz T,Stru?yńska L.Early P2X7R-dependent activation of microglia during the asymptomatic phase of autoimmune encephalomyelitis.Inflammopharmacology 2019;27(1):129-37.
29 Martin E,Amar M,Dalle C,Youssef I,Boucher C,Le Duigou C,et al.New role of P2X7 receptor in an Alzheimer’s disease mouse model.Mol Psychiatry 2019;24(1):108-25.
30 McInnes IB,Cruwys S,Bowers K,Braddock M.Targeting the P2X7 receptor in rheumatoid arthritis:biological rationale for P2X7 antagonism.Clin Exp Rheumatol 2014;32(6):878-82.
31 Baldini C,Rossi C,Ferro F,Santini E,Seccia V,Donati V,et al.The P2X7 receptor-inflammasome complex has a role in modulating the inflammatory response in primary Sj?gren’s syndrome.J Intern Med 2013;274(5):480-9.
32 Khalafalla MG,Woods LT,Camden JM,Khan AA,Limesand KH,Petris MJ,et al.P2X7 receptor antagonism prevents IL-1βrelease from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy.J Biol Chem2017;292(40):16626-37.
33马秀英,张源明,戴晨,王梦如,郭小亚,董建.P2X7受体在肾脏相关疾病中作用的研究进展.医学综述(Ma Xiuying,Zhang Yuanming,Dai Chen,Wang Mengru,Guo Xiaoya,Dong Jian.Research progress of P2X7 receptor in kidney related diseases.Medical Recapitulate)2017;23(20):3963-7.
34 Rodrigues AM,Bergamaschi CT,Fernandes MJ,Paredes-Gamero EJ,Buri MV,Ferreira AT,et al.P2X(7)receptor in the kidneys of diabetic rats submitted to aerobic training or to N-acetylcysteine supplementation[corrected].PLoS One 2014;9(6):e97452.
35 Menzies RI,Booth JWR,Mullins JJ,Bailey MA,Tam FWK,Norman JT,et al.Hyperglycemia-induced Renal P2X7 Receptor Activation Enhances Diabetes-related Injury.EbioMedicine2017;19:73-83.
36 Yan Y,Bai J,Zhou X,Tang J,Jiang C,Tolbert E,et al.P2X7receptor inhibition protects against ischemic acute kidney injury in mice.Am J Physiol Cell Physiol 2015;308(6):C463-72.
37 Franco M,Bautista-Pérez R,Cano-Martínez A,Pacheco U,Santamaría J,Del Valle Mondragón L,et al.Physiopathological implications of P2X(1)and P2X(7)receptors in regulation of glomerular hemodynamics in angiotensin II-induced hypertension.Am J Physiol Renal Physiol 2017;313(1):F9-19.
38 Müller T,Vieira RP,Grimm M,Dürk T,Cicko S,Zeiser R,et al.A potential role for P2X7R in allergic airway inflammation in mice and humans.Am J Respir Cell Mol Biol 2011;44(4):456-64.
39 Li R,Wang J,Li R,Zhu F,Xu W,Zha G,et al.ATP/P2X7-NLRP3 axis of dendritic cells participates in the regulation of airway inflammation and hyper-responsiveness in asthma by mediating HMGB1 expression and secretion.Exp Cell Res 2018;366(1):1-15.
40 Mon??o-Ribeiro LC,Faffe DS,Santana PT,Vieira FS,da Gra?a CL,Marques-da-Silva C,et al.P2X7 receptor modulates inflammatory and functional pulmonary changes induced by silica.PLoS One 2014;9(10):e110185.
41 Wang S,Zhao J,Wang H,Liang Y,Yang N,Huang Y.Blockage of P2X7 attenuates acute lung injury in mice by inhibiting NLRP3inflammasome.Int Immunopharmacol 2015;27(1):38-45.