“Salt-atory” choices for transcription: sodium chloride toward MS through BLIMP-1, FOXP3, IRF4 and SGK1 kinase Akt

More than two decades ago, a research team in the lab of David Hafler, a Yale researcher who at the time was at Harvard, discovered a type of T cell in humans that suppresses the immune system; they later found that these so-called regulatory T cells, when defective, are an underlying cause of autoimmune disease, specifically multiple sclerosis (MS). Despite many clues and informations for many years, however, the mechanism behind this dysfunction has remained unclear. In a new Yale-led study, a team of researchers finds that this loss of immune regulation is triggered by an increase in PRDM1-S, a protein involved in immune function, triggering a dynamic interaction of multiple genetic and environmental factors, including high salt uptake. The findings also reveal a new target for a universal treatment for human autoimmune disease.

Autoimmune diseases are known to be affected by genetic and environmental factors, including vitamin D deficiency and fatty acids. In an earlier study, Sumida and Hafler found that high levels of salt also contribute to the development of multiple sclerosis, an autoimmune disease of the central nervous system. Specifically, they observed that high salt induces inflammation in a type of immune cell known as CD4 T cells, while also causing a loss of regulatory T cell function. This, they found, is mediated by a salt-sensitive kinase known as SGK-1 (serum and glucocorticoid-regulated kinase 1). For the new study, researchers used RNA sequencing to compare gene expression in patients with MS with expression in healthy individuals. In patients with MS, the researchers identified upregulation, or increased expression, of a gene called PRDM1-S (primate-specific transcription factor), also known as BLIMP-1, which is involved in regulating immune function.

PRDM1-S induces expression of SGK1 independent from the evolutionarily conserved long PRDM1, which led to destabilization of forkhead box P3 (FOXP3) and T_reg dysfunction. FOXP3 plays an essential role in lineage commitment during the development of tT_reg cells in the thymus, but also in maintaining the extrathymic T_reg cell pool in mice by sustaining ‘T_reg cell signature’ gene expression. The differentiation into T helper 1-type (Th1-type), Th2-type and Th17-type T_reg cells is initiated by transcription factors. Here, the expression of T-bet promotes the differentiation of T_H1-type T_reg cells, RORγt and STAT3 promote the differentiation of Th1-type T_reg cells, and IRF4, GATA3 and STAT6 promote the differentiation of Th2-type T_reg cells. General effector T_reg cell maturation and non-lymphoid tissue resident programmes are regulated by BATF, IRF4 and GATA3.

SGK1, which interacts with the mTOR–AKT and FOXO pathways, has been implicated as playing a role in the development of multiple sclerosis and EAE. Although initially known for its role in maintaining the salt balance by inducing the production of aldosterone in renal tubule epithelial cells, the role of SGK1 in the differentiation of CD4⁺ T helper cells became evident when examining mouse Th17 cells. Here, SGK1 emerged as a pivotal driver of IL-23R expression, thereby contributing to a phenotype skewed towards Th17 cells rather than T_reg cells with potential for pathogenesis. This new aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in T_regs from individuals with MS revealed enriched activating protein-1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and T_reg dysfunction.

This effect requires p38 MAPK and SGK1 kinase signaling, is enhanced under elevated NaCl conditions and has also been demonstrated in in vitro experiments with human T_reg cells. Here, high salt exposure impaired T_reg cell function without altering TSDR methylation or FOXP3 expression, favouring a shift towards T_H1 cell differentiation which was marked by elevated T-bet expression and IFNγ production. Inhibition of SGK1, or deletion or silencing of SGK1, causes retention of unphosphorylated FOXO1 in the nucleus, which leads to an upregulation of FOXP3, CTLA4, ICOS and CD25, and restores function under high salt conditions. These data are the delving picture of the original discovery how hugh bodily salt eposure was able to modify immune reactions and to increase the risk for developing multiple sclerosis.

• Edited by Dr. Gianfrancesco Cormaci, PhD, specialista in Clinical Biochemistry.

Scientific references

Sumida TS et al. Sci Translat Med. 2024; 24(7):503-517.

Cheru N et al. Front Immunol. 2023 May 1; 14:1154575.

Axisa PP et al. Sci Transl Med. 2022; 14(675):eabl3651.