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Here, we show that combining sphingosine-1-phosphate receptor (S1PR) modulation with CNS-penetrant intranasal interferon-\u03b2 (nIFN-\u03b2) enhances therapeutic effects relative to FTY720 alone in a chronic progressive EAE model. Combined treatment reduces CNS-infiltrating immune cells, decreases pro-inflammatory cytokine production, and augments protective glial programs in vivo, as well as in human astrocyte and microglial cell lines. Transcriptomic and perturbation analyses implicate SOCS1-associated signaling as a modulatory component of treatment-induced glial responses. Together, these findings support further investigation of combinatorial FTY720\/nIFN-\u03b2 strategies targeting CNS-intrinsic inflammatory pathways in progressive MS.<\/jats:p>","DOI":"10.1038\/s41598-026-45303-9","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T05:35:39Z","timestamp":1774416939000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Interferon-\u03b2 and FTY720 ameliorate progressive CNS inflammation via SOCS1-associated astrocyte signaling"],"prefix":"10.1038","volume":"16","author":[{"given":"Thanos","family":"Tsaktanis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Beyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Nirschl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandru-Ioan","family":"Rotaru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Engleitner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupert","family":"\u00d6llinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Finnja","family":"Zuber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Peter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Zissler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivienne","family":"Tschurl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Linnerbauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"L\u00f6\u00dflein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Vandrey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Rad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Korn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0296-843X","authenticated-orcid":false,"given":"Veit","family":"Rothhammer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"issue":"2","key":"45303_CR1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1097\/01.JAA.0000651716.72042.21","volume":"33","author":"C Shull","year":"2020","unstructured":"Shull, C. et al. 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