Sirtuin 1 overexpression contributes to the expansion of follicular helper T cells in systemic lupus erythematosus and may serve as an accessible therapeutic target.

in Rheumatology (Oxford, England) by Liting He, Wei Liao, Xin Wang, Ling Wang, Qing Liang, Li Jiang, Wanyu Yi, Shuaihantian Luo, Yu Liu, Xiangning Qiu, Yaping Li, Jun Liu, Haijing Wu, Ming Zhao, Hai Long, Qianjin Lu

TLDR

  • This study looked at how a protein called SIRT1 affects the growth of a type of immune cell called Tfh cells in people with lupus. The study found that SIRT1 is more active in Tfh cells from people with lupus and that it helps Tfh cells grow. The study also found that blocking SIRT1 can stop Tfh cells from growing. The study suggests that SIRT1 could be a target for treatment in people with lupus.

Abstract

SIRT1, an NAD+-dependent deacetylase, is upregulated in CD4+ T cells from SLE patients and MRL/lpr lupus-like mice. This study aimed to explore the role of SIRT1 in follicular helper T (Tfh) cell expansion and its potential value as a therapeutic target for SLE. Frequencies of CD4+CXCR5+PD-1+ Tfh cells in peripheral blood from SLE patients and their expression of SIRT1 and B cell lymphoma 6 (BCL-6) were determined with flow cytometry. Naïve CD4+ T cells were transfected with SIRT1-expressing lentivirus and small interfering RNA (siRNA) targeting SIRT1, respectively, and then cultured under Tfh-polarizing conditions to study the impact of SIRT1 on Tfh cell differentiation. This impact was also evaluated in both CD4+ T cells and naïve CD4+ T cells by treatment with SIRT1 inhibitors (EX527 and nicotinamide) in vitro. MRL/lpr mice and pristane-induced lupus mice were treated with continuous daily intake of nicotinamide, and their lupus phenotypes (including skin rash, arthritis, proteinuria and serum anti-dsDNA autoantibodies) were compared with those of controls. Expression of SIRT1 was elevated in Tfh cells from SLE patients and was positively correlated with Tfh cell frequencies. SIRT1 expression gradually increased during Tfh cell differentiation. Overexpression of SIRT1 by lentiviral vectors significantly promoted Tfh cell differentiation/proliferation. Reciprocally, suppressing expression of SIRT1 by siRNA and inhibiting SIRT1 activity by EX-527 or nicotinamide hindered Tfh cell expansion. Continuous daily intake of nicotinamide alleviated lupus-like phenotypes and decreased serum CXCL13 in the two mouse models. SIRT1 overexpression contributed to the expansion of Tfh cells in SLE and may serve as a potential target for treatment.

Overview

  • The study explores the role of SIRT1 in follicular helper T (Tfh) cell expansion and its potential value as a therapeutic target for SLE. The study uses flow cytometry to determine the frequencies of CD4+CXCR5+PD-1+ Tfh cells in peripheral blood from SLE patients and their expression of SIRT1 and B cell lymphoma 6 (BCL-6). Naïve CD4+ T cells are transfected with SIRT1-expressing lentivirus and small interfering RNA (siRNA) targeting SIRT1, respectively, and then cultured under Tfh-polarizing conditions to study the impact of SIRT1 on Tfh cell differentiation. The study also evaluates the impact of SIRT1 on Tfh cell differentiation in both CD4+ T cells and naïve CD4+ T cells by treatment with SIRT1 inhibitors (EX527 and nicotinamide) in vitro. MRL/lpr mice and pristane-induced lupus mice are treated with continuous daily intake of nicotinamide, and their lupus phenotypes (including skin rash, arthritis, proteinuria and serum anti-dsDNA autoantibodies) are compared with those of controls. The primary objective of the study is to determine the role of SIRT1 in Tfh cell expansion and its potential value as a therapeutic target for SLE.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study identifies that SIRT1 expression is elevated in Tfh cells from SLE patients and is positively correlated with Tfh cell frequencies. SIRT1 expression gradually increases during Tfh cell differentiation. Overexpression of SIRT1 by lentiviral vectors significantly promotes Tfh cell differentiation/proliferation. Reciprocally, suppressing expression of SIRT1 by siRNA and inhibiting SIRT1 activity by EX-527 or nicotinamide hinders Tfh cell expansion. Continuous daily intake of nicotinamide alleviates lupus-like phenotypes and decreases serum CXCL13 in the two mouse models. The key findings of the study are that SIRT1 overexpression contributes to the expansion of Tfh cells in SLE and may serve as a potential target for treatment.

Implications and Future Directions

  • The study's findings have significant implications for the field of research or clinical practice. The study identifies that SIRT1 is upregulated in CD4+ T cells from SLE patients and MRL/lpr lupus-like mice, and its expression is positively correlated with Tfh cell frequencies. The study also identifies that SIRT1 overexpression contributes to the expansion of Tfh cells in SLE and may serve as a potential target for treatment. The study suggests future research directions that could build on the results of the study, explore unresolved questions, or utilize novel approaches. These include further investigation of the role of SIRT1 in Tfh cell differentiation and its potential as a therapeutic target for SLE, as well as studies of the effects of SIRT1 inhibitors on other immune cell populations and disease states.
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