Astrocyte-microglia lactate shuttle restrains microglial phenotypic transition during myelin phagocytosis in radiation-induced brain injury.

BACKGROUND: Radiation-induced brain injury (RBI) is a serious sequela in long-term survivals of patients with brain tumors or nasopharyngeal carcinoma after receiving radiotherapy. The role of multiple glial cell types in driving major RBI pathologies remains largely unclear. METHODS: The late-phase radiation response in mouse brain was profiled and analyzed using bulk tissue RNA-sequencing and single-nucleus mRNA sequencing (snRNA-seq). Glia crosstalk was investigated by using primary culture and co-culture. RESULTS: We found substantial loss of mature oligodendrocytes and microglia-derived neuroinflammation as 2 major features in late phase of RBI. Loss of oligodendrocytes coincides with the emergence of a radiation-induced reactive microglial subpopulation (RRM_1) characterized by enhanced phagocytosis activity, specialized for myelin debris clearance. Myelin debris phagocytosis induces a M2-to-M1 phenotypic transition in irradiated microglia. Astrocyte-microglia lactate shuttle (AMLS), mediated by monocarboxylate transporters (MCT4/MCT1), suppresses M1-like polarization of microglia. M2-like phenotype could be enhanced by secreted secreted phosphoprotein 1 (SPP1) via boosting AMLS. CONCLUSIONS: Taken together, we found demyelination and neuroinflammation are two intimately related features in irradiated brain. Microglia and astrocyte collectively contribute to tissue homeostasis by stably scavenging myelin/cellular debris. Our data reveal a correlative glial metabolic cascade (oligodendrocytes, microglia, and astrocytes) linked to chronic neuroinflammation. These findings provide new insights into therapeutic strategies for RBI.