IL-38 Ameliorates Skin Inflammation and Limits IL-17 Production from gamma delta T Cells

Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or gamma delta T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon gamma delta T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress gamma delta T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by gamma delta T cells. Our findings indicate a role for IL-38 in the regulation of gamma delta T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.