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.
Han, Yingying and Mora, Javier and Putyrski, Mateusz and Huard, Arnaud and da Silva, Priscila and Scholz, Anica and Elwakeel, Eiman and Lang, Guangping and Scholz, Tatjana and Schmid, Tobias and de Bruin, Natasja and Billuart, Pierre and Sala, Carlo and Burkhardt, Harald and Parnham, Michael J. and Ernst, Andreas and Brüne, Bernhard and Weigert, Andreas, Il-38 Restricts Skin Inflammation and Anti-Tumor Immunity by Limiting Il-17 Production from γδ T Cells (2018). Available at SSRN: https://ssrn.com/abstract=3213912 or http://dx.doi.org/10.2139/ssrn.3213912
This version of the paper has not been formally peer reviewed.
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