Astrocyte-Microglia Lactate Shuttle (AMLS) Restrains Microglial Phenotypic Transition During Myelin Phagocytosis in Radiation-Induced Brain Injury

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ID: 325271
2026
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Abstract
Abstract 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 remain 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 are two 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 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.
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Authors Rong Li, Anbang Ren, Weirui Chen, Anan Xu, Haifeng Jian, Weilan Zeng, Guixiang Liao, Jie Lin, Yuchao Wu, Ronghui Zheng, Huang Laiji, Kai Liao, Yin Guo, Yawei Yuan
Journal Neuro-Oncology Advances
Year 2026
DOI
10.1093/noajnl/vdag215
URL
https://doi.org/10.1093/noajnl/vdag215
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