Spatiotemporally selective ATP events from astrocytes encode injury information and guide sustained microglial response

Abstract

Brain injuries, either directly result from external assaults or are accompanied with diseases, initiate a cascade of intrinsic responses for damage management, with resident microglia as one of the key responders in the early phase of reaction. Changes in microglia including their motility and activities can be tuned according to injury intensity and position, indicating such injury information is precisely encoded and actively presented. Also, microglia in a broad area can perform sustained migration towards a transient and local injury, suggesting a signal amplification process may exist that bridge differences between injury and microglial migration in time and space. Currently, the molecular identity and underlying mechanism for injury encoding, amplification and presentation have not been fully elucidated yet, although candidate molecules like ATP are linked with both injury and microglial response. Based upon our recent technique advancement in engineering novel genetically-encoded ATP sensors, we here identified and characterized that in the cortex of awake mice in vivo, a new type of spatiotemporally selective ATP events, referred to as Inflares, was selectively evoked after brain injuries, which were actively and repeatedly generated from astrocytes in a Ca2+-dependent manner through the opening of pannexin 1 channel. Functionally, Inflares amplified local injury over time and space with their persistence and widespread distribution, and provided continuous directionality that was necessary for guiding microglial migration. Excessive Inflares in pathological injuries drove microglial dysfunction and caused secondary damage, whereas blocking Inflares successfully reversed pathological changes and benefited the outcome of ischemic stroke. Together, we identified the internal mechanism that encoded and presented injury information, and provided rational target for treating injury-related diseases.