A reciprocal glial circuit calibrates injury information and governs the tissue response balance

Brain injury elicits complex tissue responses that are dynamically regulated between activation and resolution, yet the mechanisms that govern this balance remain elusive. We show that acute injury evokes focal extracellular ATP events (Inflares) with characteristic spatiotemporal signatures that scale quantitatively with injury severity, suggesting a glial mechanism for damage calibration. We further reveal that microglia exert negative feedback on Inflares by tuning interleukin (IL)-1β output based on extracellular ATP levels and cellular state. The IL-1β signal is directly received by astrocytes through IL-1R1 and intracellular Ca²⁺-calcineurin signaling, where it converges with injury input to shape Panx1-dependent ATP release. These bidirectional interactions form a reciprocal glial circuit that enforces a balanced injury response, while disrupting the circuit destabilizes the dynamic control, impairing the cellular reactivity and worsening early injury outcomes. Our findings uncover a glial circuit and molecular players that dynamically regulate tissue injury responses.