The Molecular Mechanisms Of TAGAP And TRAF3IP2-AS1 In Autoimmune Diseases

Autoimmune diseases are casued by the attack of our immune system to our own tissues and organs,which results in tissue damage.The common autoimmune diseases include multiple sclerosis,rheumatoid arthritis,type I diabetes,psoriasis and systemic lupus erythematosus,etc.In recent years,more and more evidence show that Th17 cell abundance abnormalities and IL-17 signaling pathway changes mediate a variety of autoimmune diseases.Genome wide association study(GWAS)data show that there is a close relationship between single nucleotide polymorphisms of many genes and susceptibility to autoimmune diseases,including the variants of TAGAP(T cell activation Rho GTPase activating protein)gene and lnc RNA TRAF3IP2-AS1.Therefore,it is of great significance to explore the molecular mechanism of their involvement in the occurrence of autoimmune diseases.It is known that many single nucleotide variations of TAGAP gene are significantly associated with the susceptibility of multiple sclerosis and other autoimmune diseases,as well as the susceptibility of candidiasis,while the specific molecular mechanism is still unclear.Firstly,we find that TAGAP mediates the activation of antifungal immune signaling and the expression of inflammatory cytokines in macrophages and dendritic cells.Through the molecular mechanism study,we find that Syk recruits and activates receptor tyrosine kinase EPHB2 in specific ligands-induced antifungal immune signaling pathways.The activated EPHB2 mediates the phosphorylation of TAGAP-Y310,which promotes the recruitment of CARD9 by TAGAP and the activation of downstream signaling pathway.Th17 cells play an important role in antifungal infection.We find that due to the deficiency of antifungal innate immunity,TAGAP knockout mice show the decrease of Th17 cells differentiation in vivo.The abnormal differentiation of Th17 is closely related to the susceptibility of many autoimmune diseases.We induce experimental autoimmune encephalomyelitis(EAE)model in TAGAP heterozygous and TAGAP knockout mice,and find that TAGAP knockout mice have reduced Th17 cells,and are resistant to EAE.In addition,we find that two marketed drugs(vandetanib and dasatinib)alleviate EAE of mice by inhibiting the kinase activity of EPHB2.In conclusion,the study of this project show that the expression of TAGAP promotes the differentiation of Th17 cells and the development of EAE in mice by mediating the activation of antifungal innate immune signaling pathway and the expression of specific cytokines.At the same time,this study also suggests that TAGAP and Eph B2 are potential targets for the treatment of human multiple sclerosis.In human body,the major function of Th17 cells is to secrete IL-17 to eliminate fungal infection.However,IL-17 is an inflammatory molecule,which can promote local inflammation by mediating the activation of IL-17 signaling pathway.Therefore,the abnormality of IL-17 signaling pathway is closely related to the occurrence and development of a variety of autoimmune diseases.As an important adaptor in IL-17 signaling pathway,the single nucleotide polymorphism of TRAF3IP2(encode Act1 protein)is closely related to the susceptibility of a variety of autoimmune diseases.It has been reported that a single nucleotide variation(rs13210247)in the intron of TRAF3IP2 gene is significantly associated with the susceptibility of psoriasis in human.This SNP is located in the exon 4(A4165G)of TRAF3IP2-AS1,which is the antisense lnc RNA of TRAF3IP2.We investigate the function of TRAF3IP2-AS1 and find that it recruits SRSF10 to inhibit the expression of IRF1,which is the transcription factor of Act1,thereby inhibits the expression of Act1 and the activation of IL-17 signaling pathway.Meanwhile,we also find that the single nucleotide variation rs13210247(A4165G)of TRAF3IP2-AS1 is a gain-of-function variant,which can inhibit the expression of Act1 and the activation of IL-17 signaling pathway by enhancing the recruiting of SRSF10.In addition,we find that mouse lnc RNA E130307A14-Rik is a homologous gene of human TRAF3IP2-AS1,which also inhibits the expression of Act1 and the activation of IL-17 signaling pathway in mice.Injection of lentivirus-expressing E130307A14-Rik or SRSF10 into mice significantly alleviated the severity of psoriasis and EAE,which suggests that TRAF3IP2-AS1 and SRSF10 could be the potential targets for the treatment of human psoriasis and multiple sclerosis.In conclusion,our studies not only systematically elucidate the molecular mechanism of TAGAP and lnc RNA TRAF3IP2-AS1 in the association of susceptibility of autoimmune diseases,but also suggest that EPHB2、 TRAF3IP2-AS1 and SRSF10 could be the potential targets for the treatment of Th17 cell-related autoimmune diseases,such as psoriasis and multiple sclerosis.