2. Academic Validation
  3. CCL5/RANTES signaling in inflammation dysregulation after mild traumatic brain injury

CCL5/RANTES signaling in inflammation dysregulation after mild traumatic brain injury

  • J Biomed Sci. 2026 Jan 9;33(1):10. doi: 10.1186/s12929-025-01203-0.
Man-Hau Ho # 1 2,  Yih-Jeng Tsai # 3 4,  Yu-Hsuan Lee 1 2 5 6,  Yi-Chen Hsieh 1 2,  Chia-Hung Yen 7,  Jia-Yi Wang 8 9 10,  Thierry Burnouf 10 11 12 13 14,  Chia-Yen Chen 2,  Wen-Cheng Lin 2,  Yun Wang 15,  Yung-Hsiao Chiang 9 10 16,  Barry J Hoffer 1 2 17 18,  Szu-Yi Chou 19 20 21 22 23
Affiliations

Affiliations

  • 1 Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institute, 250 Wu-Xing Street, Taipei City, 11031, Taiwan.
  • 2 Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, 250 Wu-Xing Street, 11031.
  • 3 Department of Otolaryngology Head and Neck Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
  • 4 School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
  • 5 Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan.
  • 6 Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
  • 7 Department of Biological Science and Technology, National Pingtung University of Science and Technology, Neipu, Pingtung, 91201, Taiwan.
  • 8 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
  • 9 Department of Neurosurgery, Taipei Medical University Hospital, Taipei, 11031, Taiwan.
  • 10 Neuroscience Research Center, Taipei Medical University, Taipei, 11031, Taiwan.
  • 11 International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.
  • 12 Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.
  • 13 NeuroTMULille International Laboratory, Taipei Medical University, Taipei, Taiwan.
  • 14 International PhD Program in Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 15 Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, 350401, Miaoli County, Taiwan.
  • 16 Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
  • 17 Hoffer Consulting, Cleveland, OH, USA.
  • 18 Scientist Emeritus, National Institutes of Health, Bethesda, USA.
  • 19 Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institute, 250 Wu-Xing Street, Taipei City, 11031, Taiwan. [email protected].
  • 20 Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, 250 Wu-Xing Street, 11031. [email protected].
  • 21 Neuroscience Research Center, Taipei Medical University, Taipei, 11031, Taiwan. [email protected].
  • 22 NeuroTMULille International Laboratory, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 23 International Master Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. [email protected].
  • # Contributed equally.
PMID: 41508046 DOI: 10.1186/s12929-025-01203-0
Abstract

Background: Mild traumatic brain injury (mTBI) is the most prevalent form of brain injury. Secondary damage following mTBI contributes to neuronal degeneration by promoting neuroinflammation, amyloid accumulation, and oxidative stress (OS). Microglia exhibit dual roles after injury, contributing to both pro-inflammatory (M1) and anti-inflammation/neuroprotective (M2) responses. Targeting microglial polarization may therefore represent a therapeutic strategy for mitigating secondary damage after TBI.

Methods: A weight-drop mTBI model (30 g, 100 cm) was applied to both C57BL/6 (wild-type) and CCL5 knockout (CCL5-KO) mice. Microglial activation was assessed at 7-, 14-, 21-, and 28-days post-injury using RT-qPCR, immunohistochemistry, and western blotting. Oxidative stress in tissue was detected by Hydroxyprobe™ labeling, ROS detection, NADPH Oxidase activity assay, and antioxidant expression. Recombinant CCL5 (rCCL5) was administered intranasally to evaluate its effect on post-injury inflammation. Cortical tissue was subjected to liquid chromatography-tandem mass spectrometry (LC-MS/MS) for proteomic profiling. In vitro, BV2 microglial cells were treated with H2O2 to model OS. The effects of rCCL5 on cell viability, inflammatory gene expression, and phagocytic activity were assessed via MTT assay, immunocytochemistry, flow cytometry, and RT-qPCR. Pharmacological inhibitors targeting CCR1, CCR3, and CCR5 were used to delineate receptor-specific signaling pathways.

Results: rCCL5 significantly reduced oxidative stress in both neurons and microglia and enhanced expression of antioxidant Enzymes such as GPX1, SOD1, and SOD2 in injured cortices. Proteomic analysis revealed upregulation of immune regulatory and phagocytosis-related pathways following rCCL5 treatment. In vitro, rCCL5 conferred cytoprotection against H2O2-induced cell death and promoted M2-like microglial polarization. Blockade of CCR5, but not CCR3, abrogated CCL5-induced M2 differentiation, whereas both CCR3 and CCR5 were required for enhanced phagocytosis. CCL5-induced NFATc2 activation was mediated primarily via CCR5.

Conclusions: These findings demonstrate that CCL5 modulates microglial polarization and attenuates oxidative stress in the injured brain through a CCR5-dependent mechanism. Targeting the CCL5-CCR5 signaling axis may offer a promising therapeutic strategy for improving outcomes after mTBI.

Keywords

CCL5; CCR5 signaling; Microglia; Mild traumatic brain injury; Oxidative stress.

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