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.
Related
- Dendrimer Delivered shRNA Targeting the CCL20-CCR6 Axis Suppresses Complement-Mediated Microglial Synaptic Pruning and Ameliorates Chronic Neuroinflammation After Repetitive Traumatic Brain Injury
- Stimulating microglial neuroinflammation with amyloid-beta oligomers compatible with solid-state NMR structural characterization
- Human microglial transitions at the Aβ–tau inflection point associate with divergent pathways to dementia and resilience
- RevPert: predicting candidate drivers of transcriptomic state transitions via gallery-native reverse perturbation
- ISP Platform powered by Geneformer: Framework for Cross-Species, Sequential, and Multi-Gene In Silico Perturbation Screens with Application to iPS Cell State Transitions
BibTeX
@article{cui2026purinergic,
title = {{A purinergic receptor dominance model for microglial state transitions: balancing perturbation and restraint during neuroinflammation}},
author = {Junbo Cui and Giuseppe Bersani and Ljiljana Bukarica and Charlie Sands and Yi Dai and Minke Tang},
journal = {Frontiers in Neuroscience},
year = {2026},
month = nov,
doi = {10.3389/fnins.2026.1943067},
url = {https://www.frontiersin.org/articles/10.3389/fnins.2026.1943067},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A purinergic receptor dominance model for microglial state transitions: balancing perturbation and restraint during neuroinflammation
AU - Junbo Cui
AU - Giuseppe Bersani
AU - Ljiljana Bukarica
AU - Charlie Sands
AU - Yi Dai
AU - Minke Tang
PY - 2026
DA - 2026/11/04
JO - Frontiers in Neuroscience
DO - 10.3389/fnins.2026.1943067
UR - https://www.frontiersin.org/articles/10.3389/fnins.2026.1943067
AB - 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.
SN - 1662-453X
ER -