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G protein-coupled receptor 56 (GPR56), a potential drug target, is crucial for neuronal and glial cell function and therefore plays important roles in various neurological diseases. Here, we investigated the potential role and mechanism of GPR56 in TBI-related damage to gain new insights into the pharmacological treatment of TBI. Our study revealed that TBI caused a significant decrease in GPR56 expression and that the deletion of <jats:italic>Gpr56<\/jats:italic> exacerbated neurological function deficits and blood\u2012brain barrier (BBB) damage following TBI. Additionally, <jats:italic>Gpr56<\/jats:italic> deletion led to increased microgliosis, increased infiltration of peripheral T cells and macrophages, and increased release of cerebral inflammatory cytokines and chemokines after TBI. Furthermore, <jats:italic>Gpr56<\/jats:italic> deletion induced neuronal apoptosis, impaired autophagy, and exacerbated neurological function deficits through microglial-to-neuronal CCR5 signaling after TBI. Overall, these results indicate that <jats:italic>Gpr56<\/jats:italic> knockout exacerbates neurological deficits, neuroinflammation and neuronal apoptosis following TBI through microglial CCL3\/4\/5 upregulation targeted to CCR5, which indicates that GRP56 may be a potential new pharmacological target for TBI.<\/jats:p>","DOI":"10.1038\/s41419-025-07501-7","type":"journal-article","created":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T13:26:08Z","timestamp":1742045168000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genetic deletion of G protein-coupled receptor 56 aggravates traumatic brain injury through the microglial CCL3\/4\/5 upregulation targeted to CCR5"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8110-1481","authenticated-orcid":false,"given":"Zhuang","family":"Sha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiying","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4933-6918","authenticated-orcid":false,"given":"Chenrui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanxiang","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingqi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangyuan","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianhua","family":"Piao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9119-0115","authenticated-orcid":false,"given":"Rongcai","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4895-0085","authenticated-orcid":false,"given":"Chuang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,15]]},"reference":[{"key":"7501_CR1","first-page":"1080","volume":"1304","author":"MC Dewan","year":"2018","unstructured":"Dewan MC, Rattani A, Gupta S, Baticulon RE, Hung YC, Punchak M, et al. 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