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

  • Neuron. 2025 Nov 18:S0896-6273(25)00803-7. doi: 10.1016/j.neuron.2025.10.022.
Jinpeng Zhou  1 ,  Shuoyao Ma  1 ,  Dayun Feng  1 ,  Yang Tian  1 ,  Leiyang Li  1 ,  Hao Guo  1 ,  Yingwu Shi  1 ,  Wenxing Cui  1 ,  Jingyu Dong  1 ,  Sijia Hao  2 ,  Chengxuan Guo  1 ,  Meng Xu  1 ,  Liying Han  1 ,  Hao Bai  1 ,  Dan He  3 ,  Xiao Cui  4 ,  Lian Chen  5 ,  Xun Wu  1 ,  Fei Gao  1 ,  Qing Hu  1 ,  Ziwen Zhang  1 ,  Kai Wang  1 ,  Gaoyang Zhou  1 ,  Tian Feng  1 ,  Dongzhi Xue  1 ,  Qian Lin  1 ,  Liang Wang  1 ,  Li Gao  1 ,  Lijun Heng  1 ,  Tianzhi Zhao  1 ,  Tao Luo  1 ,  Bo Tian  1 ,  Xingye Zhang  1 ,  Wei Guo  1 ,  Zhihong Li  1 ,  Haixiao Liu  6 ,  Shunnan Ge  7 ,  Qiang Liu  8 ,  Yan Qu  9
Affiliations
  • 1. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
  • 2. Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
  • 3. Laboratory of Animal Center, Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
  • 4. Department of Neurosurgery, the First Hospital of China Medical University, Shenyang 110001, China.
  • 5. Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
  • 6. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China. Electronic address: [email protected].
  • 7. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China. Electronic address: [email protected].
  • 8. Department of Neurology, Tianjin Neurological Institute, Laboratory of Post-Neuroinjury Neurorepair and Regeneration in Central Nervous System Tianjin & Ministry of Education, Tianjin Medical University General Hospital, Tianjin 300052, China. Electronic address: [email protected].
  • 9. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China; Shaanxi Provincial Neurosurgical Medical Quality Control Center, Xi'an 710038, China; Shaanxi Provincial Brain Injury Assessment Quality Control Center, Xi'an 710038, China. Electronic address: [email protected].
PMID: 41260217 DOI: 10.1016/j.neuron.2025.10.022
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.
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