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

Cellular & Molecular Immunology volume 19, pages 738–750 (2022)Cite this article

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Abstract

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.

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Fig. 1: SIRT2 is induced in Th17 cells and promotes their differentiation.
Fig. 2: ICERγ binds to the Sirt2 promoter directly and increases its activity.
Fig. 3: SIRT2 deacetylates p70S6K and regulates the mTORC1/HIF-1α/RORγt pathway.
Fig. 4: SIRT2 inhibits IL-2 production by CD4+ T cells via deacetylation of c-Jun and histones at the Il-2 locus.
Fig. 5: Treatment with the SIRT2 inhibitor AK-7 ameliorates disease severity in adoptive transfer EAE.
Fig. 6: Treatment with the SIRT2 inhibitor AK-7 ameliorates lupus-like disease.
Fig. 7: Treatment with a SIRT2 inhibitor suppresses IL-17A and promotes IL-2 production in CD4+ T cells from patients with SLE.

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Data availability

All data are available in the main text or the Supplementary Materials.

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Funding

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); and the Société Française de Rhumatologie, the Arthur-Sachs & Monahan fellowships and the Philippe Foundation (to MS).

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Authors and Affiliations

  1. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

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

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  1. Ryo Hisada
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  2. Nobuya Yoshida
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Contributions

RH, NY, and GCT conceived and designed the study. RH, MU, CB, RB, MK, and NY performed the experiments and data analysis and interpretation. VCK and SK provided human samples. RH, NY, MS, and GCT drafted the manuscript.

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Correspondence to George C. Tsokos.

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Hisada, R., Yoshida, N., Umeda, M. et al. The deacetylase SIRT2 contributes to autoimmune disease pathogenesis by modulating IL-17A and IL-2 transcription. Cell Mol Immunol 19, 738–750 (2022). https://doi.org/10.1038/s41423-022-00874-1

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