Drug screening identifies Src/Abl inhibitor dasatinib as suppressor of IL-23 signaling in skin inflammation

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BACKGROUND: 17 cells is central to the pathogenesis of psoriasis and other autoimmune disorders. However, the intracellular mechanisms linking IL-23 signaling to effector cytokine production remain incompletely defined, limiting the development of therapeutics targeting pathways downstream of IL-23. OBJECTIVES: We elucidated signaling mechanisms connecting IL-23 stimulation to IL-17 production and identified pharmacologic inhibitors of type 3 immune responses. METHODS: We developed an in vitro model using a γδ17 T-cell line to study IL-23 responses and performed a drug-repurposing screen of US Food and Drug Administration-approved compounds. Hits were validated in primary cells. The in vivo efficacy of candidate inhibitors was evaluated in the imiquimod-induced model of skin inflammation via intraperitoneal, oral, and topical administration. Mechanistic studies assessed IL-23-dependent activation of mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 and the role of Src family kinases. RESULTS: Src/Abl kinase inhibitor dasatinib was identified as potent suppressor of IL-23-induced IL-17A production. In vivo, dasatinib treatment reduced epidermal thickening, immune cell infiltration, and the accumulation of IL-17-producing T cells in inflamed skin. Dasatinib inhibited IL-23-dependent activation of mTORC1 and mTORC2. Loss-of-function experiments revealed the Src kinase Blk (B lymphoid kinase) as a critical mediator of IL-23-induced mTORC1 activation and IL-17A production in γδ17 T cells. CONCLUSIONS: These findings define a novel IL-23-Src-mTOR signaling axis in type 3 immunity and identify Src kinase networks as promising therapeutic targets in IL-23/IL-17-driven inflammation.

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