Targeting Microglial C5aR1 with PMX205 Attenuates Neuroinflammation and Improves Neurological Recovery After Intracerebral Hemorrhage

Abstract

Activation of microglia and inflammatory response play a central role in the pathological process following intracerebral hemorrhage (ICH). In this study, single-nucleus transcriptomic and proteomic profiling was performed to investigate microglial changes after ICH. A significant upregulation of complement receptor C5aR1 was identified, particularly enriched in microglial subsets exhibiting a pro-inflammatory phenotype. The cellular localization and temporal expression dynamics of C5aR1 were validated by immunofluorescence staining, Western blotting, and quantitative PCR, demonstrating its sustained elevation in microglia after ICH. Pharmacological inhibition with the selective C5aR1 antagonist PMX205 markedly reduced the release of inflammatory cytokines, alleviated neuronal damage, and improved neurological function. Proteomic profiling and subsequent validation suggested that CCR5 may be associated with C5aR1-related inflammatory responses after ICH. Collectively, these findings suggest that C5aR1 serves as a regulatory factor in microglia-mediated neuroinflammation following ICH, and that targeting this pathway may offer a promising therapeutic strategy for hemorrhagic stroke.