{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:43:28Z","timestamp":1790117008223,"version":"4.0.1"},"update-to":[{"DOI":"10.1371\/journal.pntd.0013170","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000}}],"reference-count":83,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T00:00:00Z","timestamp":1749427200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 82373492"],"award-info":[{"award-number":["No. 82373492"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Special Project for Medical and Health Talents of Jilin Provincial Department of Finance","award":["JLSWSRCZX2025-096"],"award-info":[{"award-number":["JLSWSRCZX2025-096"]}]},{"DOI":"10.13039\/100007847","name":"Natural Science Foundation of Jilin Province","doi-asserted-by":"publisher","award":["NO.YDZJ202201ZYTS030"],"award-info":[{"award-number":["NO.YDZJ202201ZYTS030"]}],"id":[{"id":"10.13039\/100007847","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Sporotrichosis is a subcutaneous mycosis caused by members of the genus <jats:italic>Sporothrix<\/jats:italic>, among which <jats:italic>Sporothrix globosa<\/jats:italic> (<jats:italic>S. globosa<\/jats:italic>) is the predominant etiological agent in Asia. T cell immunity plays crucial roles in fungal infections, yet the local T cell immune profile in sporotrichosis lesions remains unclear. IL-18, a pleiotropic cytokine capable of modulating T cell responses, is also poorly understood in host defense against <jats:italic>S. globosa<\/jats:italic>.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methodology\/principal findings<\/jats:title>\n<jats:p>qPCR, western blot, and IHC\/mIHC were employed to profile IL-18, IL-18 BP, caspase-1 and IL-18R axis, along with Th1,Th2, and Th17 cells and their specific cytokines in sporotrichosis lesions versus healthy skin. Cellular sources of IL-18 in the lesions were identified via mIHC, and IL-18 production from keratinocyte\/PBMCs exposed to <jats:italic>S. globosa<\/jats:italic> in vitro was tested by qPCR and western blot. Flow cytometry was performed to evaluate the role of IL-18 in Th2 polarization in the PBMCs-<jats:italic>S. globosa<\/jats:italic> coculture system. Lesional skin exhibited hyperactivated IL-18 signaling, marked by upregulated IL-18, caspase-1, and IL-18R, alongside decreased IL-18 BP. IL-18 was primarily released by dermal dendritic cells and Langerhans cells, rather than keratinocytes. A mixed Th1\/Th2\/Th17 microenvironment with Th2 predominance correlated strongly with prolonged disease duration. Strikingly, IL-18 synergistically interacted with Th1-derived IL-2 to establish a self-reinforcing Th2 loop, as evidenced by the strong correlation between lesional IL-4 and IL-18 levels (<jats:italic>r<\/jats:italic>\u2009=\u20090.70) and the concomitant upregulation of IL-18\/IL-2 during <jats:italic>S. globosa<\/jats:italic>-induced Th2 expansion in PBMCs\u2014an effect reversed by IL-18\/IL-2 neutralizing antibodies. Critically, this Th2 skewing was mechanistically dependent on NF-\u03baB signaling, as demonstrated through pharmacological pathway inhibition.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions\/significance<\/jats:title>\n<jats:p>This study unveils the dual role of IL-18 in human sporotrichosis caused by <jats:italic>S. globosa<\/jats:italic>\u2014amplifying both Th1 and Th2 responses but ultimately driving pathogenic Th2 polarization through IL-2 crosstalk. Our work identifies IL-18\/IL-2\/NF-\u03baB axis as a key Th2-polarizing mechanism driving chronicity in this disease. Targeting this axis could recalibrate anti-fungal immunity, offering translational strategies for this subcutaneous disease.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0013170","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T17:56:03Z","timestamp":1749491763000},"page":"e0013170","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["IL-18 favors Th2 responses in sporotrichosis caused by Sporothrix globosa, prolonging the course of the 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