Low-dose PFOS exposure exacerbates rheumatoid arthritis via SIRT2-PAD4-mediated macrophage pyroptosis

Perfluorooctane sulfonic acid (PFOS), a ubiquitous and persistent environmental pollutant, has been linked to diverse diseases in epidemiological studies; however, its role in rheumatoid arthritis (RA) progression at low exposure levels remains to be elucidated. In this article, we found a significant positive association between serum PFOS concentrations and RA prevalence, based on data from the National Health and Nutrition Examination Survey (NHANES). Consistent with these findings, chronic exposure to an environmentally relevant dose of PFOS via drinking water for 6 weeks aggravated joint swelling, inflammatory cell infiltration, and bone erosion in a collagen-induced arthritis (CIA) mouse model. Mechanistically, peptidyl arginine deiminase 4 (PAD4), identified as a significantly upregulated protein in synovial fluid through proteomic profiling, is induced by PFOS in macrophages. Consistently, the knockdown of PAD4 was shown to attenuate both PFOS-triggered macrophage pyroptosis in vitro and CIA progression in vivo. Further analyses demonstrated that PFOS suppressed the epigenetic regulator SIRT2, thereby inducing PAD4 transcriptional upregulation. Therefore, macrophage-specific overexpression of SIRT2 rescued PFOS-promoted pyroptosis and mitigated joint inflammation and structural damage in CIA mice. Taken together, these findings demonstrate that low dose PFOS exposure exacerbates RA progression through activation of a SIRT2-PAD4 pathway-dependent macrophage pyroptosis. This not only provides a novel mechanistic link between environmental pollutants and chronic inflammatory joint diseases but also highlights SIRT2/PAD4 axis as a potential therapeutic target for mitigating PFOS-associated immunopathology.