{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T14:30:42Z","timestamp":1792161042906,"version":"4.4.0"},"reference-count":188,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NINDS","award":["1R1NS138528-01"],"award-info":[{"award-number":["1R1NS138528-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The Complement C3a Receptor (C3aR) plays a multifaceted role along the varying temporal phases of brain injury following cerebral ischemia. C3aR is a G-protein-coupled receptor (GPCR) that binds to its ligand, C3a an anaphylatoxin generated during activation of the complement cascade. During ischemia, complement is activated as part of the initial inflammatory response, with C3aRs playing a time-dependent role in both brain injury and repair mechanisms. In the acute phase (minutes to hours post-ischemia), C3aR activation promotes the recruitment of immune cells and the release of chemokines and cytokines, driving blood\u2013brain barrier (BBB) permeability and brain edema. During the subacute phase (hours to days post-ischemia), C3aR continues to modulate immune cell activity, worsening secondary brain injury, although emerging evidence suggests that C3aR activation in this phase may also aid in the clearance of cellular debris and cell survival. In the chronic phase (days to weeks post-ischemia), chronically elevated C3aR activity can prolong neuroinflammation and impair recovery, whereas controlled C3aR signaling in the subacute\/chronic phase can activate reparative pathways (e.g., microglial phagocytosis, astrocyte trophic support). As a result, targeting the C3aR requires careful timing to optimize its benefits. Given the dual impact of C3aR activation, which serves to exacerbate injury in the acute phase but supports repair beginning in the subacute and chronic phases, a targeted therapeutic approach should focus on context- and time-dependent modulation of the C3a\/C3aR axis. This strategy would involve blocking the C3aR during the acute phase to reduce inflammation and BBB breakdown while controlling C3a signaling in later phases to promote tissue repair.<\/jats:p>","DOI":"10.3390\/cells14181440","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T16:27:33Z","timestamp":1757953653000},"page":"1440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Complex Role of the Complement C3a Receptor (C3aR) in Cerebral Injury and Recovery Following Ischemic Stroke"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2011-0955","authenticated-orcid":false,"given":"Naseem","family":"Akhter","sequence":"first","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ateeq","family":"Lambay","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1432-460X","authenticated-orcid":false,"given":"Reema","family":"Almotairi","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Prince Fahad bin Sultan Chair for Biomedical Research, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1095-5455","authenticated-orcid":false,"given":"Abdullah","family":"Hamadi","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Prince Fahad bin Sultan Chair for Biomedical Research, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanchan","family":"Bhatia","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2410-574X","authenticated-orcid":false,"given":"Saif","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, USA"},{"name":"Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ 85013, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew F.","family":"Ducruet","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, USA"},{"name":"Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ 85013, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1177\/17474930211065917","article-title":"World Stroke Organization (WSO): Global stroke fact sheet 2022","volume":"17","author":"Feigin","year":"2022","journal-title":"Int. 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