LncRNA Xist may regulate Th17 cell differentiation through TDP43-IRF3 pathway in neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorder (NMOSD) is a central nervous system inflammatory demyelinating disease with significantly high incidence in women, but the mechanism of gender bias is unknown. The process of X chromosome inactivation regulated by lncRNA Xist is important for dose compensation of immune-related X-linked genes between the sexes. This study aimed to explore a Xist-related pathway which might lead to the female preponderance of NMOSD. Some studies have shown that lncRNA Xist may interact with transactive response DNA-binding protein (TARDBP, also known as TDP43). TDP43 can be cleaved by caspase-3 into its active form, TDP35, which might increase the level of interferon regulatory factor 3 (IRF3), while IRF3 may promote the proliferation of Th17 cells. Our preliminary study conducted in peripheral blood mononuclear cell of female NMOSD patients showed the same trend with above literatures. Based on those studies and our preliminary results, we hypothesized that in the CD4+ na??ve T cells of female NMOSD patients, the downregulation of lncRNA Xist decreased its interaction with TDP43 and released more TDP43 to be cleaved to its active form TDP35, thereby inhibits IRF3 degradation, and then promotes the differentiation and proliferation of Th17 cells and induced the inflammation of female NMOSD patients. This study would shed further light on the immune regulation mechanism related to lncRNA Xist, which may play a key role in the sex bias of NMOSD.