Inhibition of C5aR1 alleviates early brain injury after subarachnoid hemorrhage by reducing STAT3 phosphorylation and attenuating neuroinflammation

Subarachnoid hemorrhage is a severe type of cerebral hemorrhage, with neuroinflammation being the main driving factor. The C5a-C5aR1 axis can mediate the inflammatory response, but its mechanism of action in SAH remains unclear. We established in vivo and in vitro models of SAH and treated them with the C5aR1 inhibitor PMX53 or the STAT3 Inhibitor STAT3-IN-13. We detected C5aR1 expression, levels of inflammatory factors, microglial polarization, and neuronal Apoptosis using Western blotting, ELISA, TUNEL, and immunofluorescence. The expression of C5aR1 in the brains of SAH mice (peaking at 24 h) and in the cerebrospinal fluid (CSF) of patients was upregulated, which was associated with poor prognosis. PMX53 can improve neurological function, reduce edema and neuronal Apoptosis, and transform microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type. PMX53 and STAT3-IN-13 inhibit JAK/STAT3-p65 phosphorylation, reduce TNF-α/IL-1β, and increase TGF-β/IL-10. C5a promotes STAT3 phosphorylation through C5aR1, thereby exacerbating neuroinflammation, making C5aR1 a potential therapeutic target.