Abstracto
- Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptor(s) remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. Therefore, we investigated cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38-knockout (IL-38 KO) mice showed delayed disease resolution due to exacerbated IL-17-mediated inflammation, which was reversed by administration of mature IL-38. Mechanistically, IL-38 antagonized X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1), which was upregulated upon γδ T cell activation to feed-forward amplify IL-17 production. Heightened activation of tumor-infiltrating γδ T cells was also observed in IL-38 KO oncogene-driven mammary carcinoma, accompanied by attenuated tumor growth. Our findings, which are supported by clinical data, highlight the connection between auto-inflammation and anti-tumor immunity and indicate IL-38 as a potential therapeutic target under these conditions.