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Recent works have highlighted the critical role of myeloid cells in MS, contributing to both neurodegeneration and repair. FK506-binding protein 5 (FKBP5), a co-chaperone of the glucocorticoid receptor and regulator of stress responses, has been implicated in MS pathology, yet its mechanistic role remains poorly understood. Here, we show that FKBP5 expression is elevated in monocytes and dendritic cells from the cerebrospinal fluid of people with MS and enriched in microglial nodules. Additionally, we show that genetic ablation or pharmacological inhibition of Fkbp5 in microglia and macrophages enhances myelin uptake and degradation via phagolysosomal pathways and attenuates interferon-gamma (IFNg)-induced transcriptional programs. In the experimental autoimmune encephalomyelitis (EAE) model of MS, systemic treatment with the selective FKBP5 inhibitor SAFit2 reduced immune cell infiltration, dampened microglial activation, and suppressed IFNg signaling, resulting in improved clinical outcomes. Taken together, our data identify FKBP5 as a critical mediator of myeloid cell-driven neuroinflammation, and a promising therapeutic target in MS.<\/jats:p>","DOI":"10.1186\/s12974-026-03703-8","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T08:13:22Z","timestamp":1770711202000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["FKBP5 regulates interferon signaling leading to myeloid cell activation in multiple sclerosis"],"prefix":"10.1186","volume":"23","author":[{"given":"Cinthia","family":"Gonzalez Cruz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Gibson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Kita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narendra V.","family":"Sankpal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignazio S.","family":"Piras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Cantoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"key":"3703_CR1","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/S0140-6736(23)01473-3","volume":"403","author":"D Jakimovski","year":"2024","unstructured":"Jakimovski D, Bittner S, Zivadinov R, Morrow SA, Benedict RH, Zipp F, et al. Multiple sclerosis. Lancet. 2024;403:183\u2013202. https:\/\/doi.org\/10.1016\/S0140-6736(23)01473-3.","journal-title":"Lancet"},{"key":"3703_CR2","doi-asserted-by":"publisher","unstructured":"Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. New England Journal of Medicine. Massachusetts Medical Society; 2018 [cited 2025 Apr 30];378:169\u201380. https:\/\/doi.org\/10.1056\/NEJMRA1401483\/SUPPL_FILE\/NEJMRA1401483_DISCLOSURES.PDF","DOI":"10.1056\/NEJMRA1401483\/SUPPL_FILE\/NEJMRA1401483_DISCLOSURES.PDF"},{"issue":"7","key":"3703_CR3","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/s41583-023-00709-6","volume":"24","author":"F Dist\u00e9fano-Gagn\u00e9","year":"2023","unstructured":"Dist\u00e9fano-Gagn\u00e9 F, Bitarafan S, Lacroix S, Gosselin D, Nature Publishing Group. Roles and regulation of microglia activity in multiple sclerosis: insights from animal models. 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