The Function And Underlying Mechanism Of IL-17 Family Cytokines In Autoimmune Diseases

Upon infection or tissue damage,immune system is mobilized to initiate the inflammatory process.Chronic inflammation is closely linked to autoimmune diseases,allergic and cancers.Interleukin-17（IL-17）family cytokines,identified relatively recently,play important role in host defense and immune response.The IL-17 family consists of six members（IL-17A to IL-17F）.Among them,as the signature cytokines of Th17 cell,IL-17A and IL-17F share the highest similarity at the amino acid sequence and have been well studied,and play essential function in inflammation and autoimmunity.IL-17E,also called IL-25,is involved in Th2 related immune responses such as asthma and host defense against parasite infection.However,the biological functions of IL-17B,IL-17C and IL-17D remain largely unknown.In this study,we investigated the functions of IL-17C and IL-17D,respectively,in ConA-induced autoimmune hepatitis and DSS-induced colitis by employing Il17c^-/-and Il17d^-/-mice.Here we demonstrate the critical role of IL-17C/IL-17RE axis in ConA-induced hepatitis.Elevated IL-17C expression was detected in liver samples of both human and mouse autoimmune hepatitis,Il17c^-/-mice and its receptor Il17re^-/-mice suffered less liver damage.Mechanistically,IL-17C augment the expression of IL-2 by intrahepatic CD4⁺T cells to promote the pathogenesis of hepatitis,as revealed by reduced cell number,impaired cell activation and compromised function in Il17c deficient mice.Thus,our work may provide a novel target for the treatment of this disease.On the other hand,we report that IL-17D expression is required for steady-state and colitis condition IL-22 production from intestine ILC3,genetic ablation of IL-17D resulted in exacerbated colitis and microbiota dysbiosis,administration of IL-17D partially restored the phenotype in IL-17D deficient mice.RNA-seq data showed that IL-17D appears to maintain the stability of ILC3.IL-17D in non-hematopoietic cells play an essential role in DSS-induced colitis by BM chimeras.Moreover,we tried to identify the functional receptor for IL-17D from RAW264.7 cells by IP-MS.Taken together,our results uncover IL-17D with vital function in regulating intestinal homeostasis of IL-22-producing ILC3 and mucosal defense.