Role of P2X7 Receptors in Immune Responses During Neurodegeneration

Overview

Journal Front Cell Neurosci

Specialty Cell Biology

Date 2021 Jun 14

PMID 34122013

Citations 26

Authors

Agatha Oliveira-Giacomelli

Lyvia Lintzmaier Petiz

Roberta Andrejew

Natalia Turrini

Jean Bezerra Silva

Ulrich Sack

Henning Ulrich

Affiliations

Soon will be listed here.

Abstract

P2X7 receptors are ion-gated channels activated by ATP. Under pathological conditions, the extensive release of ATP induces sustained P2X7 receptor activation, culminating in induction of proinflammatory pathways with inflammasome assembly and cytokine release. These inflammatory conditions, whether occurring peripherally or in the central nervous system (CNS), increase blood-brain-barrier (BBB) permeability. Besides its well-known involvement in neurodegeneration and neuroinflammation, the P2X7 receptor may induce BBB disruption and chemotaxis of peripheral immune cells to the CNS, resulting in brain parenchyma infiltration. For instance, despite common effects on cytokine release, P2X7 receptor signaling is also associated with metalloproteinase secretion and activation, as well as migration and differentiation of T lymphocytes, monocytes and dendritic cells. Here we highlight that peripheral immune cells mediate the pathogenesis of Multiple Sclerosis and Parkinson's and Alzheimer's disease, mainly through T lymphocyte, neutrophil and monocyte infiltration. We propose that P2X7 receptor activation contributes to neurodegenerative disease progression beyond its known effects on the CNS. This review discusses how P2X7 receptor activation mediates responses of peripheral immune cells within the inflamed CNS, as occurring in the aforementioned diseases.

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References

Hardy J, Higgins G . Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992; 256(5054):184-5. DOI: 10.1126/science.1566067. View

Yang F, Zhao K, Zhang X, Zhang J, Xu B . ATP Induces Disruption of Tight Junction Proteins via IL-1 Beta-Dependent MMP-9 Activation of Human Blood-Brain Barrier . Neural Plast. 2016; 2016:8928530. PMC: 5067334. DOI: 10.1155/2016/8928530. View

Eyo U, Peng J, Swiatkowski P, Mukherjee A, Bispo A, Wu L . Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus. J Neurosci. 2014; 34(32):10528-40. PMC: 4200107. DOI: 10.1523/JNEUROSCI.0416-14.2014. View

Di Virgilio F . Purinergic signalling in the immune system. A brief update. Purinergic Signal. 2008; 3(1-2):1-3. PMC: 2096765. DOI: 10.1007/s11302-006-9048-5. View

Ribeiro D, Oliveira-Giacomelli A, Glaser T, Arnaud-Sampaio V, Andrejew R, Dieckmann L . Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology. Mol Psychiatry. 2020; 26(4):1044-1059. PMC: 7738776. DOI: 10.1038/s41380-020-00965-3. View

Di Virgilio F, Schmalzing G, Markwardt F . The Elusive P2X7 Macropore. Trends Cell Biol. 2018; 28(5):392-404. DOI: 10.1016/j.tcb.2018.01.005. View

Grassi F . The P2X7 Receptor as Regulator of T Cell Development and Function. Front Immunol. 2020; 11:1179. PMC: 7297980. DOI: 10.3389/fimmu.2020.01179. View

Mori T, Wang X, Aoki T, Lo E . Downregulation of matrix metalloproteinase-9 and attenuation of edema via inhibition of ERK mitogen activated protein kinase in traumatic brain injury. J Neurotrauma. 2002; 19(11):1411-9. DOI: 10.1089/089771502320914642. View

Wanhainen K, Jameson S, Borges da Silva H . Self-Regulation of Memory CD8 T Cell Metabolism through Extracellular ATP Signaling. Immunometabolism. 2019; 1(1). PMC: 6699786. DOI: 10.20900/immunometab20190009. View

10.

Amadio S, Parisi C, Piras E, Fabbrizio P, Apolloni S, Montilli C . Modulation of P2X7 Receptor during Inflammation in Multiple Sclerosis. Front Immunol. 2017; 8:1529. PMC: 5694754. DOI: 10.3389/fimmu.2017.01529. View

11.

Tang Y, Le W . Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Mol Neurobiol. 2015; 53(2):1181-1194. DOI: 10.1007/s12035-014-9070-5. View

12.

Willis C, Garwood C, Ray D . A size selective vascular barrier in the rat area postrema formed by perivascular macrophages and the extracellular matrix. Neuroscience. 2007; 150(2):498-509. DOI: 10.1016/j.neuroscience.2007.09.023. View

13.

Kim J, Kim J, Yu Y, Kim D, Kim K . Recruitment of pericytes and astrocytes is closely related to the formation of tight junction in developing retinal vessels. J Neurosci Res. 2008; 87(3):653-9. DOI: 10.1002/jnr.21884. View

14.

Yip L, Woehrle T, Corriden R, Hirsh M, Chen Y, Inoue Y . Autocrine regulation of T-cell activation by ATP release and P2X7 receptors. FASEB J. 2009; 23(6):1685-93. PMC: 2718802. DOI: 10.1096/fj.08-126458. View

15.

Cheewatrakoolpong B, Gilchrest H, Anthes J, Greenfeder S . Identification and characterization of splice variants of the human P2X7 ATP channel. Biochem Biophys Res Commun. 2005; 332(1):17-27. DOI: 10.1016/j.bbrc.2005.04.087. View

16.

Ratajczak M, Mack A, Bujko K, Domingues A, Pedziwiatr D, Kucia M . ATP-Nlrp3 Inflammasome-Complement Cascade Axis in Sterile Brain Inflammation in Psychiatric Patients and its Impact on Stem Cell Trafficking. Stem Cell Rev Rep. 2019; 15(4):497-505. PMC: 6647482. DOI: 10.1007/s12015-019-09888-1. View

17.

Borges da Silva H, Beura L, Wang H, Hanse E, Gore R, Scott M . The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8 T cells. Nature. 2018; 559(7713):264-268. PMC: 6054485. DOI: 10.1038/s41586-018-0282-0. View

18.

Oliveira-Giacomelli A, M Albino C, de Souza H, Correa-Velloso J, de Jesus Santos A, Baranova J . P2Y6 and P2X7 Receptor Antagonism Exerts Neuroprotective/ Neuroregenerative Effects in an Animal Model of Parkinson's Disease. Front Cell Neurosci. 2019; 13:476. PMC: 6856016. DOI: 10.3389/fncel.2019.00476. View

19.

Paolicelli R, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P . Synaptic pruning by microglia is necessary for normal brain development. Science. 2011; 333(6048):1456-8. DOI: 10.1126/science.1202529. View

20.

Shiratori M, Tozaki-Saitoh H, Yoshitake M, Tsuda M, Inoue K . P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways. J Neurochem. 2010; 114(3):810-9. DOI: 10.1111/j.1471-4159.2010.06809.x. View