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Since IL-6 is important for blood-brain barrier support and its deficiency has been shown to facilitate <jats:italic>Cn<\/jats:italic> brain invasion, we investigated the impact of IL-6 on systemic <jats:italic>Cn<\/jats:italic> infection in vivo, focusing on central nervous system (CNS) colonization and glial responses, specifically microglia and astrocytes. IL-6 knock-out (IL-6<jats:sup>\u2212\/\u2212<\/jats:sup>) mice showed faster mortality than C57BL\/6 (Wild-type) and IL-6<jats:sup>\u2212\/\u2212<\/jats:sup> supplemented with recombinant IL-6 (rIL-6; 40 pg\/g\/day) mice. Despite showing early lung inflammation but no major histological differences in pulmonary cryptococcosis progression among the experimental groups, IL-6<jats:sup>\u2212\/\u2212<\/jats:sup> mice had significantly higher blood and brain tissue fungal burden at 7-days post infection. Exposure of cryptococci to rIL-6 in vitro increased capsule growth. In addition, IL-6<jats:sup>\u2212\/\u2212<\/jats:sup> brains were characterized by an increased dystrophic microglia number during <jats:italic>Cn<\/jats:italic> infection, which are associated with neurodegeneration and senescence. In contrast, the brains of IL-6-producing or -supplemented mice displayed high numbers of activated and phagocytic microglia, which are related to a stronger anti-cryptococcal response or tissue repair. Likewise, culture of rIL-6 with microglia-like cells promoted high fungal phagocytosis and killing, whereas IL-6 silencing in microglia decreased fungal phagocytosis. Lastly, astrogliosis was high and moderate in infected brains removed from Wild-type and IL-6<jats:sup>\u2212\/\u2212<\/jats:sup> supplemented with rIL-6 animals, respectively, while minimal astrogliosis was observed in IL-6<jats:sup>\u2212\/\u2212<\/jats:sup> tissue, highlighting the potential of astrocytes in containing and combating cryptococcal infection. Our findings suggest a critical role for IL-6 in <jats:italic>Cn<\/jats:italic> CNS dissemination, neurocryptococcosis development, and host defense.<\/jats:p>","DOI":"10.1186\/s12974-024-03237-x","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T04:02:13Z","timestamp":1727668933000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["IL-6 deficiency accelerates cerebral cryptococcosis and alters glial cell responses"],"prefix":"10.1186","volume":"21","author":[{"given":"Marta","family":"Reguera-Gomez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa E.","family":"Munzen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed F.","family":"Hamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia L.","family":"Charles-Ni\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis R.","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,27]]},"reference":[{"issue":"3","key":"3237_CR1","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1128\/iai.17.3.634-638.1977","volume":"17","author":"JB Neilson","year":"1977","unstructured":"Neilson JB, Fromtling RA, Bulmer GS. 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