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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A weight-drop mTBI model (30\u00a0g, 100\u00a0cm) 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\u2122 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 H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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 H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      -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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings demonstrate that CCL5 modulates microglial polarization and attenuates oxidative stress in the injured brain through a CCR5-dependent mechanism. Targeting the CCL5\u2013CCR5 signaling axis may offer a promising therapeutic strategy for improving outcomes after mTBI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-025-01203-0","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T02:44:21Z","timestamp":1767926661000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["CCL5\/RANTES signaling in inflammation dysregulation after mild traumatic brain injury"],"prefix":"10.1186","volume":"33","author":[{"given":"Man-Hau","family":"Ho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yih-Jeng","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hsuan","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chen","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Hung","family":"Yen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Yi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Burnouf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Cheng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Hsiao","family":"Chiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry J.","family":"Hoffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szu-Yi","family":"Chou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"1203_CR1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1159\/000326771","volume":"19","author":"Z Zhang","year":"2012","unstructured":"Zhang Z, Zhang ZY, Wu Y, Schluesener HJ. 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