Project description:Cooperative role of Lymphotoxin β Receptor and Tumor Necrosis Factor Receptor p55 in murine liver regeneration (PHx Control vs Enbrel)
Project description:Systemic lupus erythematosus (SLE) is an autoimmune disorder with systemic inflammation, autoantibody accumulation and organ damage. The abnormalities of double-negative (DN) T cells are considered as an important commander of SLE. Neddylation, an important type of protein post-translational modification (PTM), has been well-proved to regulate T cell-mediated immune response. However, the function of neddylation in SLE remains largely unexplored. Here, we reported that neddylation inactivation with MLN4924 or genetic abrogation of Ube2m in T cells prevented SLE development for decreased DN T cell accumulation. Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells, contributing to the apoptosis of the accumulated DN T cells for Fas mutation. Then double knockout (KO) lupus-prone mice (Ube2m-/-Bim-/-lpr) were generated and results showed that loss of Bim interrupted the improvement of DN T cell apoptosis and the consequential relieved lupus symptoms for Ube2m KO. Our findings identified that neddylation inactivation promoted Bim-mediated apoptosis of DN T cells and prevented lupus progress. Clinically, we also found the percentages of DN T cells were improved accompanied with reduced apoptosis of DN T cells in SLE patients. Moreover, the neddylation of Cullin1 was higher while Bim level was decreased in SLE patients compared with healthy control. Meantime, the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients. Together, these findings provide the first evidence of the neddylation role in lupus development, suggesting a novel therapeutic strategy for lupus.
Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-α in vitro and that Siglec-H ko mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease. For microarray experiments gene expression profiles of total splenic cells from two wt and Siglec-H ko mice 26 weeks after infection with luciferase expressing murine Cytomegalovirus (5x105 pfu) or from two uninfected wt and Siglec-H ko control mice were analyzed
Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-α in vitro and that Siglec-H ko mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease.
Project description:Psip1/p75 binds to Hox genes and colocalizes with Mll1 and in Psip1 KO MEFs Mll1 occupancy is reduced over Hox genes Psip1/p75 ChIP using A300-848 abtibody (recognises p75 isoform of Psip1) and Mll1 ChIP from WT and Psip1 KO MEFs ChIP-chip