Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; Special Key Laboratory of Oral Diseases Research, Higher Education Institutions of Guizhou Province, Zunyi Medical University, 563006 Zunyi, Guizhou, China; School of Stomatology, Zunyi Medical University, 563006 Zunyi, Guizhou, China.
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; Faculty of Microbiology, University of Costa Rica, 2060 San José, Costa Rica.
Cell Rep. 2019 Apr 16;27(3):835-846.e5. doi: 10.1016/j.celrep.2019.03.082.
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 γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.
白细胞介素-38 (IL-38) 是白细胞介素 1 家族的细胞因子，在慢性炎症中发挥作用。然而，其主要的细胞靶标和受体仍然不清楚。IL-38 在皮肤中高度表达，在银屑病患者中下调。我们报告了在咪喹莫特诱导的银屑病进展过程中 IL-38 的细胞靶标的研究。在该模型中，IL-38 敲除 (IL-38 KO) 小鼠的疾病缓解延迟，伴有加剧的 IL-17 介导的炎症，而成熟的 IL-38 或 γδ T 细胞受体阻断抗体的给药可逆转这种情况。从机制上讲，X 连锁白细胞介素 1 受体辅助蛋白样 1 (IL1RAPL1) 在 γδ T 细胞激活时上调，以正向放大 IL-17 的产生，并且 IL-38 抑制 γδ T 细胞 IL-17 产生也需要 IL1RAPL1。因此，银屑病 IL1RAPL1 KO 小鼠的炎症和 γδ T 细胞的 IL-17 产生减少。我们的研究结果表明，IL-38 通过 IL1RAPL1 在调节 γδ T 细胞激活方面发挥作用，这对自身炎症性疾病有影响。
