2. Academic Validation
  3. Circulating Ly6Chigh monocyte-derived S100A4+ macrophages exacerbate neuroinflammation and impede recovery of traumatic brain injury

Circulating Ly6Chigh monocyte-derived S100A4+ macrophages exacerbate neuroinflammation and impede recovery of traumatic brain injury

  • Brain Behav Immun. 2026 Jan 26:134:106472. doi: 10.1016/j.bbi.2026.106472.
Zhichao Lu 1,  Chenxing Wang 1,  Yongqi Zhu 1,  Jingwei Zhao 2,  Yaxuan Gu 3,  Xingjia Zhu 1,  Weiquan Liao 1,  Jue Zhu 1,  Rui Jiang 4,  Suyin Feng 5,  Tianxi Chen 3,  Xudong Zhao 3,  Ziheng Wang 6,  Qianqian Liu 7,  Peipei Gong 8,  Yang Yang 9
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China.
  • 2 Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Biliary Tract Disease Research, Research Institute of Biliary Tract Disease, Shanghai 200092, China.
  • 3 Department of Emergency Medicine, Affiliated Hospital of Nantong University, No.20 Xisi Road, Chongchuan District, Nantong City, Jiangsu Province 226001, China.
  • 4 Department of Neurosurgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu 226001, China.
  • 5 Department of Neurosurgery, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Address: 299 Fuguo Road, Donghai County, Lianyungang City, Jiangsu Province 223000, China; Cardio-Cerebral Vascular Disease Prevention and Treatment Innovation Center, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), 299 Fuguo Road, Donghai County, Lianyungang City, Jiangsu Province 223000, China; Donghai Intelligent Medical Innovation Center, Kangda College of Nanjing Medical University, 88 Chunhui Road, Huaguoshan Avenue, Haizhou District, Lianyungang City, Jiangsu Province 222000, China.
  • 6 MOE Frontier Science Centre for Precision Oncology, University of Macau, Macau SAR, China. Electronic address: [email protected].
  • 7 Department of Neurosurgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu 226001, China. Electronic address: [email protected].
  • 8 Department of Neurosurgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu 226001, China. Electronic address: [email protected].
  • 9 Department of Emergency Medicine, Affiliated Hospital of Nantong University, No.20 Xisi Road, Chongchuan District, Nantong City, Jiangsu Province 226001, China; Department of Chemistry, School of Science, China Pharmaceutical University, Nanjing City, Jiangsu Province 226001, China. Electronic address: [email protected].
PMID: 41605306 DOI: 10.1016/j.bbi.2026.106472
Abstract

Traumatic brain injury (TBI) is now recognized as a systemic disease, yet the molecular and cellular mechanisms involved in the systemic immune response to TBI remain unclear. To address these limitations, we collected the brains and peripheral blood mononuclear cells (PBMCs) from the acute phase of TBI mice and performed single-cell RNA Sequencing (scRNA-seq). Here, we identify a population of S100A4+ macrophages originating from circulating Ly6Chigh monocytes that infiltrate brain tissue following TBI via the CCL4-CCR1 axis, thereby exacerbating brain injury. Further mechanistic studies suggest that enhanced SPP1 output from S100A4+ macrophages following TBI triggers a microglial response via the CD44 receptor and exacerbates neuroinflammation. IRF7, as a key transcription factor (TF), drives the activation of S100A4+ macrophages following TBI, leading to the corresponding neuroinflammation and neurological deficits. An FDA-approved clinical drug, ursodeoxycholic acid, acts as an IRF7 antagonist to block the activation of S100A4+ macrophages, thereby suppressing neuroinflammation and accelerating the recovery of neurological function in TBI mice.

Keywords

IRF7; Monocyte/macrophage; Neuroinflammation; Single-cell RNA sequencing; Traumatic brain injury; Ursodeoxycholic acid.

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