Fluoride exposure has been shown to affect immune cell subsets and immune function, but its impact on macrophage polarization remains unclear. This study investigates the effects of low fluoride exposure on macrophage polarization and its underlying mechanisms through epidemiological surveys, animal experiments, and in vitro cell experiments. In the population-based epidemiological survey, we used mass cytometry to assess the impact of low fluoride exposure (0.570–2.027 mg/L) in the environment on human immune cell populations following the current water improvement and fluoride reduction measures. A rat fluorosis model was established by treating rats with sodium fluoride (NaF) in drinking water at concentrations of 0 mg/L, 5 mg/L, 10 mg/L, 25 mg/L, and 50 mg/L for 90 days., and morphological changes were assessed by hematoxylin–eosin (H&E) staining and transmission electron microscopy in the spleen of rats. Flow cytometry was used to analyze the proportion of macrophage subtypes in the spleen, while Western blot and immunofluorescence were performed to detect the expression of mitochondrial autophagy-related proteins. An M1 macrophage model was constructed in vitro by inducing THP-1 cells, and the effects of fluoride on macrophage-related cell markers and cytokines were assessed using flow cytometry and ELISA, respectively, following intervention with an autophagy inhibitor. Mitochondrial membrane potential and mitochondrial–lysosomal colocalization are analyzed through flow cytometry and confocal microscopy. The study aims to investigate the role of mitophagy in sodium fluoride-induced macrophage polarization. Epidemiological investigations revealed that low fluoride increases the proportion of blood monocytes, as well as the expression levels of CD68 (a macrophage surface marker), CD86 (an M1 macrophage marker), and the inflammatory cytokine IFN-γ in peripheral blood mononuclear cells (PBMCs). In the rats of NaF-treated groups, splenic tissues exhibited inflammatory infiltration, mitochondrial swelling, and increased autophagosome formation. Moreover, low fluoride activated the PINK1/Parkin-mediated mitophagy pathway, promoting an increase in the M2/M1 macrophage ratio. In vitro experiments further confirmed that autophagy inhibitors reversed the NaF-induced increase in the M2/M1 macrophage ratio. This study demonstrates that low fluoride induces inflammatory responses in the body and drives M1 macrophage polarization toward M2 macrophages via mitophagy. These findings highlight the potential immunological risks associated with low fluoride and provide mechanistic insights into the interplay among fluoride, mitophagy, and macrophage polarization.

Background: Stroke is a major cause of death globally and the leading cause in China. Excessive fluoride exposure has been linked to cardiovascular conditions related to stroke risk factors such as hypertension, atherosclerosis, dyslipidemia, and cardiomyopathy. However, evidence supporting the association between fluoride exposure and stroke risk is limited. Methods: We constructed an ecological study in Changwu Town, Heilongjiang Province, China, a typical endemic fluorosis area caused by excessive fluoride exposure from drinking water. We collected demographic data, stroke prevalence, and mortality information from 2017 to 2021. Fluoride exposure data were obtained from the national monitoring project on endemic fluorosis. Water fluoride concentrations were measured using the standardized methods. Trend changes in stroke rates were assessed using annual percentage change (APC). Differences in stroke rates among fluoride exposure groups were analyzed using chi-square tests. Results: From 2017 to 2021, the all-ages and age-standardized stroke prevalence rates of permanent residents in Changwu Town increased year by year, while the all-ages and age-standardized mortality rates did not change significantly. The prevalence rates of stroke were significantly higher in endemic fluorosis areas compared to non-endemic areas (p < 0.001). Stratifying the population into tertile groups based on the water fluoride cumulative exposure index (WFCEI) revealed statistically significant differences in stroke prevalence rates (p < 0.001), showing a dose–response relationship with the WFCEI. However, the all-ages and age-standardized mortality rates of stroke were not found to be related to fluoride exposure. Conclusions: Long-term excessive fluoride exposure from drinking water may increase the risk of stroke prevalence, indicating fluoride overexposure as a potential risk factor for stroke.