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.
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).
