C5aR1+ microglia exacerbate neuroinflammation and cerebral edema in acute brain injury

Abstract

Microglia rapidly respond to acute brain injury and contribute to neuroinflammation that drives cerebral edema, a major cause of mortality and disability in stroke and traumatic brain injury (TBI). However, microglial heterogeneity complicates precise therapeutic targeting because specific disease-associated subtypes remain poorly characterized. Here, we define a previously unrecognized C5a receptor 1 (C5aR1)-expressing microglial subtype enriched in human cerebral edema tissue from decompressive surgery for TBI and intracerebral hemorrhage (ICH). In preclinical models, C5aR1⁺ microglia engage locally and peripherally derive C5a to amplify neuroinflammation, drive neurotoxic astrocyte polarization, and recruit neutrophils, leading to cerebral edema. Genetic ablation of microglial C5ar1 or its pharmacological inhibition with an Food and Drug Administration (FDA)-approved antagonist attenuates cerebral edema in both TBI and ICH. These findings delineate the role of C5aR1⁺ microglia in neuroinflammatory cascades and cerebral edema following acute brain injury, indicating C5aR1 as a potential therapeutic target.

Keywords: C5aR1(+) microglia; cerebral edema; microglial heterogeneity; neurotoxic astrocytes; neutrophils recruitment.