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Previously, we demonstrated that controlled cortical impact in mice, a well-established experimental model of TBI, causes acute neuroinflammatory changes, including upregulation of interferon-\u03b2 (IFN-\u03b2) and other type I interferon (IFN-I)-related genes in the injured cortex and hippocampus. Early inhibition of IFN-\u03b2 signaling, either through intracerebroventricular administration of an anti-type I IFN receptor antibody or use of global IFN-\u03b2 knockout mice (IFN-\u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ), attenuates post-traumatic neuroinflammation and neurodegeneration and improves neurological outcomes for up to 28 days postinjury (dpi), with the knockout model showing more robust and sustained protective effects. However, the consequences of sustained suppression of these pathways after TBI have not been studied. Here, we examine the long-term effects of IFN-\u03b2 deficiency on microglial activation, neuropathology, and neurological function during the chronic phase post-TBI (60\u201390 dpi). Transcriptomic analysis of isolated microglia from wild-type mice after TBI revealed persistent upregulation of IFN-I and other key neuroinflammatory genes, including classical pro-inflammatory and disease-associated microglia (DAM) at both 60 and 90 dpi. The IFN-I pathway was significantly attenuated in IFN-\u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice at these later timepoints. However, IFN-\u03b2 deficiency did not significantly alter the trauma-induced upregulation of DAM markers, indicating selectivity of chronic IFN-\u03b2 modulation on injury-induced microglia-reactive phenotypes. Moreover, although IFN-\u03b2 deficiency significantly attenuated pro-inflammatory phenotypes at 60 dpi, it enhanced the injury-mediated downregulation of homeostatic microglial genes at 90 dpi. In addition, no significant reduction in lesion volume or fine motor deficits was observed in IFN-\u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice at chronic timepoints, although chronic post-traumatic cognitive impairment was attenuated. These findings suggest that global IFN-\u03b2 deficiency has complex, time-dependent effects on chronic outcomes following TBI; although it improves cognitive function, it further suppresses homeostatic microglia that may partially limit long-term therapeutic benefits.\n                  <\/jats:p>","DOI":"10.1177\/08977151261434894","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T05:13:47Z","timestamp":1774934027000},"page":"1681-1699","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Interferon-\u03b2 Deficiency Selectively Modulates Chronic Microglial Pathways after Traumatic Brain Injury"],"prefix":"10.1177","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0924-9449","authenticated-orcid":false,"given":"James P.","family":"Barrett","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8548-1170","authenticated-orcid":false,"given":"Rebecca J.","family":"Henry","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, Maryland, USA."},{"name":"School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Vaida","sequence":"additional","affiliation":[{"name":"Harrisburg University of Science and Technology, Harrisburg, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari Ann","family":"Shirey","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie N.","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan I.","family":"Faden","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan A.","family":"Stoica","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, Maryland, USA."},{"name":"VA Maryland Health Care System, Baltimore VA Medical Center, Baltimore, Maryland, 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