The Epigenetic Regulator Sirtuin-1 Modulates T-Helper 17 Cell Differentiation in Axial Spondyloarthritis

Sarah Unterberger¹, Patrizia Fasching², Elisabeth Fliesser¹, Angelika Lackner³, Christian Dejaco², Winfried Graninger³, Martin Stradner² and Johannes Fessler^4,5, ¹Div. of Rheumatology and Immunology, Medical University of Graz, Graz, Austria, ²Department of Rheumatology and Immunology, Medical University of Graz, Graz, Austria, ³Rheumatology and Immunology, Medical University of Graz, Graz, Austria, ⁴Dep. of Rheumatology and Immunology, Medical University of Graz, Graz, Austria, ⁵Department of Neurology, Harvard Medical School, Boston, MA

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: T cells and spondylarthropathy

Session Information

Date: Tuesday, October 23, 2018

Title: Spondyloarthritis Including Psoriatic Arthritis – Basic Science Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: The NAD⁺ -dependent protein/histone deacetylase Sirtuin 1 (SIRT1) acts as an epigenetic regulator and has recently been reported to be involved in the development of murine T_H17 cells. Here, we investigated the role of SIRT1 in polarization of human naïve T-cells in axial Spondyloarthritis (SpA).

Methods: We recruited 23 SpA patients [mean age 45 (±14); 26% female] and 11 healthy controls (HC) [mean age 39 (±11); 55% female]. In vitro differentiation of naïve CD4⁺ T cells under T_H17 cell- or regulatory T cell (Treg) polarizing conditions was performed. SIRT1 function was modulated using an inhibitor (Ex-527) or activator (Cay10602) of SIRT1 activity. IL-17 producing Th17 cells, CD25⁺FoxP3⁺ Tregs, and SIRT1 protein levels were measured by flow cytometry.

Results: In SpA patients disease activity measured by Ankylosing Spondylitis Disease Activity Score (ASDAS) correlated positively with T_H17 polarization [corr_coeff=0.549, p=0.023], and negatively with Treg polarization [corr_coeff=-0.489, p=0.064]. SIRT1 protein levels were higher in SpA patients as compared to HC in naïve CD4⁺ T cells [mean fluorescence intensity, SpA: 1293 (±447) vs. HC: 984 (±410), p=0.077] and CD4⁺ memory T cells [SpA: 1528 (±527) vs. HC: 1097 (±510), p=0.035].
Modulation of SIRT1 activity with SIRT1 inhibitor (Ex) during T_H17 differentiation in SpA patients decreased the level of T_H17 polarized cells significantly [T_H17: 6.28% (2.89-11.80) vs. T_H17_Ex: 3.42 (1.79-8.21), p≤0.001]. Treatment of T_H17 differentiation culture with SIRT1 activator (Cay) showed an enhancing effect on T_H17 polarization [T_H17: 6.28% (2.89-11.80) vs. T_H17_Cay: 9.55% (4.17-16.20), p≤0.001].

Conclusion: Our data suggest that the epigenetic regulator SIRT1 is involved in SpA pathogenesis by regulating the potential of naïve T-cells to differentiate towards the T_H17 lineage.

Disclosure: S. Unterberger, None; P. Fasching, None; E. Fliesser, None; A. Lackner, None; C. Dejaco, None; W. Graninger, None; M. Stradner, None; J. Fessler, None.

To cite this abstract in AMA style:

Unterberger S, Fasching P, Fliesser E, Lackner A, Dejaco C, Graninger W, Stradner M, Fessler J. The Epigenetic Regulator Sirtuin-1 Modulates T-Helper 17 Cell Differentiation in Axial Spondyloarthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/the-epigenetic-regulator-sirtuin-1-modulates-t-helper-17-cell-differentiation-in-axial-spondyloarthritis/. Accessed .

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