Role of P2X7 Receptors in Immune Responses During Neurodegeneration

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.

Keywords: P2X7 receptors; blood brain barrier; microglia; neurodegeneration; peripheral immune system.

FIGURE 1

P2X7 receptors in peripheral immune cells and IL-1β release. (A) Dying cells release ATP. ATP binds and activates P2X7 receptors, which induces Ca²⁺ influx and K⁺ efflux. Intracellular Ca²⁺ concentration increase induces the formation of large pores by P2X7 receptors and pannexin-1, both allowing the release of more ATP. This results in augmented extracellular ATP concentration and increased activation of P2X7 receptors, providing positive feedback effects. K⁺ efflux induces NLRP3 inflammasome assembly and the formation of more pannexin-1 channels. NLRP3 inflammasome assembly activates caspase-1, which cleaves pro-IL-1β into IL-1β and promotes its release. Caspase-1 also cleaves the inhibitory gasdermin (GSDMD)-D-C into the reactive GSDMD-D-N, that interacts with membrane phospholipids to form a pore that allows IL-1β release. This release could also occur through microvesicles, exosomes or endosomes (not shown). (B) Bone marrow stem cells can differentiate into (1) eosinophils, basophils, neutrophils, (2) monocytes, (4) dendritic cells, (5) T and B lymphocytes. (2) Activation of the P2X7 receptor in monocytes induces the release of MMP-9, which can induce disruption of BBB, and IL-1β liberation. (3,4) P2X7 receptor activation induces the differentiation of monocytes into macrophages and stimulates the release of IL-1β and TNF-α from monocytes, macrophages, and dendritic cells. (4) Released IL-1β stimulates the migration of dendritic cells. (5) In T lymphocytes, P2X7 receptor activation may: release MMP-9, induce the migration of these cells, favor differentiation into CD4⁺ or CD8⁺ cells before leaving the thymus, stabilizes its binding to dendritic cells and promote cell death, if necessary. IL-1β released by dendritic cells through P2X7 receptor stimulation activates CD4⁺ cells and (6) differentiation of these cells into T helper (Th) 1 and 17, and T follicular helper cells (Tfh). (7) Activation of P2X7 receptors in CD8⁺ cells promotes activation and survival of these cells, while IL-1β released by dendritic cells primes CD8⁺ cells. (8) P2X7 receptor expression is essential for differentiation of T cells into CD8⁺ cells. Created with BioRender.com.

FIGURE 2

The P2X7 receptor in the process of Blood-Brain Barrier permeabilization during neurodegenerative diseases. (A) Blood-Brain Barrier permeabilization through P2X7 receptor signaling begins with cellular damage, which triggers cell death and consequently ATP release into the CNS microenvironment (1). ATP content above physiologic ranges activates P2X7 receptors in microglial cells (2), which in turn leads to the production and release of IL-1β and other cytokines and chemokines (3). Moreover, the active ATP/P2X7 receptor pathway augments metalloproteinase (MMP) activities, causing TJ and BM protein degradation and consequently BBB destabilization (4). The outcome of these combined events is the peripheral immune cell invasion of the CNS. Since T cells and neutrophils express P2X7 receptors, the amount of ATP released by the damaged cells can also activate this receptor in these cells. The result is the shedding activation of adhesion proteins and the production and release of cytokines and MMPs, promoting an inflammatory and invasive feedback mechanism (5). In neurodegenerative diseases, the neuronal death process induces the release of high concentrations of ATP into the extracellular milieu. (B) In AD pathogenesis, ATP binds to P2X7 receptors that are overexpressed in microglial cells. The microglial activation depends on P2X7 receptor expression/activity to react against Aβ peptides. P2X7 receptor stimulates the release of IL-1β and chemokines that contribute to increased BBB permeability, resulting in chemotaxis of neutrophil and CD8⁺ cells. (C) In PD, α-synuclein aggregates contribute to dopaminergic neuronal death, increasing ATP levels and P2X7 overactivation. α-synuclein can bind to P2X7 receptors expressed in microglial cells. Both α-synuclein and P2X7 receptors are associated with increased release of IL-1β and chemokines, indicating an enhanced neuroinflammatory scenario in PD. This IL-1β secretion is associated with induction of MMP-9 release, resulting in BBB dysfunction. Under condition of BBB dysfunction and increased chemokine levels, T cells are chemoattracted and infiltrate brain parenchyma. T cells can recognize α-synuclein epitopes, release high amounts of ATP and present upregulation of P2X7 receptor activity, contributing to PD worsening. (D) The demyelinating character of MS is also associated with increased ATP levels and P2X7 receptor overactivation. P2X7 receptor expression and activity are upregulated in reactive astrocytes and contribute to the release of chemokines and peripheral immune cell chemotaxis. Pericytes also express P2X7 receptors that mediate the interaction between endothelial cells and pericytes and contribute to BBB integrity. Increased numbers of perivascular macrophages are associated with disease progression, and P2X7 receptor functions in this process remain unknown. MS exhibits infiltrating T cells and monocytes, expressing P2X7 receptors that contribute to the autoimmune attack and disease progression. (?) Hypothesis of P2X7 receptor involvement in perivascular macrophages, yet to be elucidated. Created with BioRender.com.