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Microglia, the resident immune cells of the central nervous system, orchestrate responses to ischemic injury and critically influence neurovascular remodeling, axonal reorganization, and functional recovery. Emerging evidence indicates that inflammatory preconditioning can reprogram microglial responses to subsequent insults, yet the exact intracellular signaling pathways mediating this adaptive state remain incompletely defined. Here, we used a chemogenetic approach to selectively activate Gq signaling in microglia employing a microglia\u2010specific DREADD mouse model. This strategy mimics Gq\u2010coupled receptor activation in microglia in the absence of peripheral immune engagement. Pre\u2010ischemic Gq activation significantly reduced infarct sizes at 24\u2009h after experimental stroke in female mice and at 7\u2009days in both sexes. Morphological analyses revealed that Gq\u2010conditioned microglia exhibited increased structural complexity, adopting a highly ramified, spatially compact phenotype and higher CD68 expression, indicating increased phagocytic activity. Transcriptional profiling demonstrated that Gq activation primes autophagy\u2010related defense pathways in microglia, resulting in upregulation of interferon\u2010stimulated genes 7\u2009days after stroke in both sexes. Together, our findings identify Gq signaling as a key modulatory pathway capable of reprogramming microglial phenotype and enhancing stroke recovery. These results highlight the plasticity of microglial signaling networks and support targeted modulation of microglial Gq pathways.<\/jats:p>","DOI":"10.1002\/glia.70209","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T04:40:23Z","timestamp":1786164023000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gq Signaling in Microglia Triggers Interferon Responses and Improves Outcome After Ischemic Stroke"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7347-6099","authenticated-orcid":false,"given":"Lynn","family":"Bitar","sequence":"first","affiliation":[{"name":"Department of Neurology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Luise","family":"Brehme","sequence":"additional","affiliation":[{"name":"Institute for Synaptic Neuroscience, Center for Molecular Neurobiology (ZMNH) University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Oldenburg","sequence":"additional","affiliation":[{"name":"Institute for Synaptic Neuroscience, Center for Molecular Neurobiology (ZMNH) University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Isla","family":"Cainzos","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Kaul","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Nuclear Medicine University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Mummert","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Nuclear Medicine University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Borggrewe","sequence":"additional","affiliation":[{"name":"Independent Bioinformatics Consultant  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Oertner","sequence":"additional","affiliation":[{"name":"Institute for Synaptic Neuroscience, Center for Molecular Neurobiology (ZMNH) University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Magnus","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.06.014"},{"key":"e_1_2_11_4_1","unstructured":"Almeida F. 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