Modulation of Microglial Function by ATP-Gated P2X7 Receptors: Studies in Rat, Mice and Human

Abstract

P2X receptors are a family of seven ATP-gated ion channels that trigger physiological and pathophysiological responses in a variety of cells. Five of the family members are sensitive to low concentrations of extracellular ATP, while the P2X6 receptor has an unknown affinity. The last subtype, the P2X7 receptor, is unique in requiring millimolar concentrations to fully activate in humans. This low sensitivity imparts the agonist with the ability to act as a damage-associated molecular pattern that triggers the innate immune response in response to the elevated levels of extracellular ATP that accompany inflammation and tissue damage. In this review, we focus on microglia because they are the primary immune cells of the central nervous system, and they activate in response to ATP or its synthetic analog, BzATP. We start by introducing purinergic receptors and then briefly consider the roles that microglia play in neurodevelopment and disease by referencing both original works and relevant reviews. Next, we move to the role of extracellular ATP and P2X receptors in initiating and/or modulating innate immunity in the central nervous system. While most of the data that we review involve work on mice and rats, we highlight human studies of P2X7R whenever possible.

Keywords: ATP; CNS diseases; P2X7; innate immunity; membrane permeabilization; microglia; purinergic receptors; tumor microenvironment.

Figure 1

P2X signaling in microglia. Extracellular ATP evokes influx of Na⁺ and Ca²⁺ and efflux of K⁺ through P2X7Rs embedded in the plasmalemmal membrane. ATP-gated efflux of K⁺ is also thought to involve additional channels; at present, the identity of these channels is unknown but may involve 2–pore K⁺ channels. The decrease in [K⁺]_i results in influx of Cl⁻ and the maturation and release of the proinflammatory cytokine IL–1β. Activation of P2X7Rs also increases membrane permeabilization of large organic cations like YO-PRO1, decreases phagocytosis, and initiates phosphatidylserine (PS) exposure on the cell surface. While YO-PRO1 permeates the P2X7R pore, other pathways (marked with a “?”) are also thought to play a role.

Figure 2

Model for microglial-driven neuroinflammation. Neuroinflammation can be subdivided into acute and chronic phases. Acute neuroinflammation is characterized by activation of resident immune cell populations, release of proinflammatory mediators including cytokines/chemokines, infiltration of peripheral immune cells to assist in the immune response, and phagocytic activity to reduce cellular debris. When inflammation persists past the initial injury event and homeostasis is not maintained, chronic neuroinflammation commences. This phase is characterized by sustained microglial activation and gliosis measured by heightened release of proinflammatory cytokines/chemokines, reduced phagocytosis, and neurodegeneration. Created with BioRender.com accessed on 8 January 2024.