Microglia Attenuate Neuroinflammation After Subarachnoid Hemorrhage by Modulating Astrocyte Phenotypic Transformation via the RARα/Mafb/Msr1 Pathway.

Neuroinflammation mediated by microglia-astrocyte interactions significantly contributes to secondary brain injury after subarachnoid hemorrhage (SAH). Retinoic acid receptor alpha (RARα) has emerged as a potential modulator of neuroinflammation. However, its specific mechanisms in the interaction between microglia and astrocytes after SAH are not yet known. This study investigated whether RARα activation might alleviate neuroinflammation post-SAH by regulating microglial-astrocytic crosstalk via the Mafb/Msr1/PI3K-Akt signaling axis. An in vivo SAH model in male Sprague-Dawley rats was established through endovascular perforation. In vitro, a microglia-astrocyte co-culture system was subjected to oxyhemoglobin treatment to mimic SAH conditions. The RARα-specific agonist Am80 was administered to activate RARα signaling. Key molecular markers (Mafb, Msr1, and PI3K/Akt), pro-/anti-inflammatory cytokines, and glial activation phenotypes were evaluated via western blotting and immunofluorescence. Functional recovery was assessed with neurobehavioral tests. Pathway-specific inhibitors were used for mechanistic validation. RARα activation markedly attenuated neuroinflammation, enhanced neurological outcomes in SAH rats, significantly decreased levels of pro-inflammatory factors, and inhibited neuroinflammation mediated by microglia. Mechanistically, Am80 was found to upregulate the transcription factor Mafb and its downstream target Msr1, thereby triggering PI3K/Akt phosphorylation. This cascade inhibited NF-κB-mediated pro-inflammatory cytokine release and enhanced anti-inflammatory factors. Critically, blockade of PI3K/Akt or knockdown of Mafb/Msr1 abolished the anti-inflammatory effects of Am80. In addition, the inflammatory factor receptors TNF-αR and IL6R were demonstrated to be important mediators of microglia and astrocyte interaction. RARα activation mitigates SAH-induced neuroinflammation by modulating microglial-astrocyte interactions through the Mafb/Msr1/PI3K-Akt pathway. Our findings identified RARα as a promising therapeutic target for ameliorating neuroinflammation and improving recovery after SAH.