The deacetylase SIRT2 contributes to autoimmune disease pathogenesis by modulating IL-17A and IL-2 transcription  

作　　者：Ryo Hisada Nobuya Yoshida Masataka Umeda Catalina Burbano Rhea Bhargava Marc Scherlinger Michihito Kono Vasileios C.Kyttaris Suzanne Krishfield George C.Tsokos 

机构地区：[1]Department of Medicine,Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA,USA

出　　处：《Cellular & Molecular Immunology》2022年第6期738-750,共13页中国免疫学杂志（英文版）

基　　金：This work was supported by NIH grant R37 AI49954(to GCT);the Uehara memorial foundation(to RH);the 2019 Gilead Sciences Research Scholars Program in Rheumatology(to NY);the SociétéFrançaise de Rhumatologie,the Arthur-Sachs&Monahan fellowships and the Philippe Foundation(to MS).

摘　　要：Aberrant IL-17A expression together with reduced IL-2 production by effector CD4^(+)T cells contributes to the pathogenesis of systemic lupus erythematosus(SLE).Here,we report that Sirtuin 2(SIRT2),a member of the family of NAD^(+)-dependent histone deacetylases,suppresses IL-2 production by CD4^(+)T cells while promoting their differentiation into Th17 cells.Mechanistically,we show that SIRT2 is responsible for the deacetylation of p70S6K,activation of the mTORC1/HIF-1α/RORγt pathway and induction of Th17-cell differentiation.Additionally,SIRT2 was shown to be responsible for the deacetylation of c-Jun and histones at the Il-2 gene,resulting in decreased IL-2 production.We found that the transcription factor inducible cAMP early repressor(ICER),which is overexpressed in T cells from people with SLE and lupus-prone mice,bound directly to the Sirt2 promoter and promoted its transcription.AK-7,a SIRT2 inhibitor,limited the ability of adoptively transferred antigen-specific CD4^(+)T cells to cause autoimmune encephalomyelitis in mice and limited disease in lupus-prone MRL/lpr mice.Finally,CD4^(+)T cells from SLE patients exhibited increased expression of SIRT2,and pharmacological inhibition of SIRT2 in primary CD4^(+)T cells from patients with SLE attenuated the ability of these cells to differentiate into Th17 cells and promoted the generation of IL-2–producing T cells.Collectively,these results suggest that SIRT2-mediated deacetylation is essential in the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new SLE therapies.

关 键 词：SIRT2 Systemic lupus erythematosus IL-17A IL-2 

分 类 号：R392[医药卫生—免疫学]