Background and Aims Systemic lupus erythematosus (SLE) is an autoimmune disorder that is characterised by the presence of autoantibodies and immune dysregulation. The pathogenesis of SLE has not been elucidated. The induction of epigenetic changes by environmental factors such as diet may also be relevant. A high-salt diet is considered an important contributor to cardiovascular and renal diseases, and recent research has indicated that a high-salt diet can induce autoimmunity.

Methods In this study, the effects of high salt on various immune cells and in MLR/lpr mice were observed, and the underlying mechanisms were investigated by flow cytometry, high-throughput sequencing, DNA methylation map, ChIP-QPCR.

Results In this study, high salt (sodium chloride, NaCl), under physiological conditions, was demonstrated to increase the differentiation of Tfh. A high-salt diet markedly increased lupus features in MRL/lpr mice. The mechanism is NaCl-induced DNA demethylation via the recruitment of the hydroxytransferase Ten-Eleven Translocation 2 (TET2). Gene silencing of TET2 obviously diminished NaCl-induced Tfh cell polarisation in vitro. In addition, the gene expression of sh2d1a, map3k1, spn and stat5b was enhanced after NaCl treatment, consistent with the findings in lupus CD4⁺T cells. However, only spn was directly regulated by TET2, and spn was not the sole target for NaCl.

Conclusions High-salt treatment promotes SLE in mice and the underlying mechanism might be NaCl enhancing Tfh cell differentiation by TET2 inducing global and gene specific DNA demethylation. Our findings not only explain the epigenetic mechanisms of high-salt induced autoimmunity but also provide an attractive molecular target for intervention strategies of SLE.