A purinergic receptor dominance model for microglial state transitions: balancing perturbation and restraint during neuroinflammation

Abstract

Microglia show substantial functional heterogeneity during neuroinflammatory responses, yet the upstream mechanisms through which they interpret extracellular perturbation-associated signals and transition between functional states remain incompletely understood. Purinergic signaling is well positioned to serve as such an environmental sensing system because ATP is released rapidly from stressed or damaged cells and is subsequently metabolized to adenosine, generating an extracellular purine landscape that changes with the magnitude and persistence of tissue stress. We propose a Purinergic Receptor Dominance Model for microglial state transitions during neuroinflammation. Microglial responses are shaped by the changing balance among ATP- and adenosine-sensitive receptor systems. P2Y12-associated signaling supports physiological surveillance; P2X4 contributes to early injury responses; and A1 and A2A receptors provide temporally layered adenosine-linked regulation. Persistent or severe stress may recruit P2X7-associated inflammatory amplification. Under the high-adenosine conditions that can accompany prolonged stress or hypoxia, A2B-linked signaling may also become relevant. The model focuses on the upstream receptor systems through which microglia may gauge the intensity, duration, and metabolic context of tissue stress. It is presented as a testable organizing hypothesis that can be evaluated, refined, or rejected experimentally.