Tregs are key mediators of renal dysfunction induced by low-dose fluoride exposure

Against the backdrop of generally reduced fluoride exposure levels in the current environment, the immune barrier function, as the core of the body's defense system, has attracted significant attention for its role in immune regulation under fluoride exposure. The kidneys, serving as a key target organ for Tregs-mediated immune homeostasis, rely on Foxp3 acetylation as a core regulatory mechanism. However, the role of Tregs in fluoride-induced renal injury remains unclear. In this cross-sectional study, we collected data from 336 residents in areas with low-to-moderate fluoride exposure (water fluoride concentration: 0.89-2.66 mg/L). We measured the following parameters: urinary fluoride, urinary creatinine (Ucr), microalbumin (MALB), and N-acetyl-β-d-glucosaminidase (NAG) levels. In addition, we assessed the proportions of CD3⁺, CD3⁺CD4⁺, CD3⁺CD8⁺T cells and regulatory T cells (Tregs) in peripheral blood mononuclear cells, and measured the expression of silent information regulator 1 (SIRT1) in Tregs. Furthermore, a rat model of fluorosis was established by administering fluoride in drinking water at concentrations of 5, 10, 25, and 50 mg/L for 12 weeks. We measured urinary fluoride levels, examined the changes in Tregs within peripheral blood and kidney tissues, and quantified the expression of SIRT1 and histone acetyltransferase (P300) in Tregs. Subsequently, in vitro-prepared rat Tregs were administered via tail vein injection to evaluate their therapeutic effect on renal injury induced by low-dose fluoride exposure. Multivariate logistic regression analysis indicated that among the population with low water fluoride exposure (<1.5 mg/L), elevated urinary fluoride levels were associated with an increased risk of abnormal MALB and NAG levels. Multivariate linear regression demonstrated that elevated urinary fluoride levels led to decreased proportions of CD3⁺, CD3⁺CD4⁺, and CD3⁺CD8⁺ cells, while increasing the proportion of Tregs. Tregs adoptive transfer effectively alleviated fluoride-induced renal inflammation and improved pathological damage in both glomeruli and tubules. Simultaneously, low fluoride exposure reduced IL-2 expression levels in Tregs in both peripheral blood and kidney tissues. Furthermore, low fluoride exposure inhibited SIRT1 in human peripheral Tregs and decreased SIRT1 and P300 levels in rat peripheral and renal Tregs. These findings demonstrate that Tregs mediate renal dysfunction induced by low-level fluoride exposure, potentially through acetylation-mediated regulation. The suppression of IL-2 levels may thereby affect Tregs activation.