2. Academic Validation
  3. Microglia aggravate white matter injury via C3/C3aR pathway after experimental subarachnoid hemorrhage

Microglia aggravate white matter injury via C3/C3aR pathway after experimental subarachnoid hemorrhage

  • Exp Neurol. 2024 Jun 10:379:114853. doi: 10.1016/j.expneurol.2024.114853.
Lei Yang 1,  Jinpeng Wu 1,  Fan Zhang 2,  Lifang Zhang 3,  Xianhui Zhang 3,  Jian Zhou 2,  Jinwei Pang 1,  Bingqing Xie 4,  Huangfan Xie 4,  Yong Jiang 5,  Jianhua Peng 6
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, China; Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, China.
  • 2 Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, China; Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, China.
  • 3 Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, China.
  • 4 Institute of Brain Science, Southwest Medical University, Luzhou, China.
  • 5 Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, China; Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, China; Institute of Brain Science, Southwest Medical University, Luzhou, China; Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, China. Electronic address: jiangyong@swmu.edu.cn.
  • 6 Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, China; Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, China; Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital, Southwest Medical University, Luzhou, China. Electronic address: pengjianhua@swmu.edu.cn.
PMID: 38866102 DOI: 10.1016/j.expneurol.2024.114853
Abstract

The activation of glial cells is intimately associated with the pathophysiology of neuroinflammation and white matter injury (WMI) during both acute and chronic phases following subarachnoid hemorrhage (SAH). The complement C3a receptor (C3aR) has a dual role in modulating inflammation and contributes to neurodevelopment, neuroplasticity, and neurodegeneration. However, its impact on WMI in the context of SAH remains unclear. In this study, 175 male C57BL/6J mice underwent SAH through endovascular perforation. Oxyhemoglobin (oxy-Hb) was employed to simulate SAH in vitro. A suite of techniques, including immunohistochemistry, transcriptomic Sequencing, and a range of molecular biotechnologies, were utilized to evaluate the activation of the C3-C3aR pathway on microglial polarization and WMI. Results revealed that post-SAH abnormal activation of microglia was accompanied by upregulation of complement C3 and C3aR. The inhibition of C3aR decreased abnormal microglial activation, attenuated neuroinflammation, and ameliorated WMI and cognitive deficits following SAH. RNA-Seq indicated that C3aR inhibition downregulated several immune and inflammatory pathways and mitigated cellular injury by reducing p53-induced death domain protein 1 (Pidd1) and Protein kinase RNA-like ER kinase (PERK) expression, two factors mainly function in sensing and responding to cellular stress and endoplasmic reticulum (ER) stress. The deleterious effects of the C3-C3aR axis in the context of SAH may be related to endoplasmic reticulum (ER) stress-dependent cellular injury and inflammasome formation. Agonists of PERK can exacerbate the cellular injury and neuroinflammation, which was attenuated by C3aR inhibition after SAH. Additionally, intranasal administration of C3a during the subacute phase of SAH was found to decrease astrocyte reactivity and alleviate cognitive deficits post-SAH. This research deepens our understanding of the complex pathophysiology of WMI following SAH and underscores the therapeutic potential of C3a treatment in promoting white matter repair and enhancing functional recovery prognosis. These insights pave the way for future clinical application of C3a-based therapies, promising significant benefits in the treatment of SAH and its related complications.

Keywords

C3; ER stress; Inflammasome; Subarachnoid hemorrhage; White matter injury.

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