Dissecting the molecular pathways through which long-chain PFAS disrupts dendritic cell maturation

Per- and polyfluoroalkyl substances (PFAS) have been associated with impaired vaccine responsiveness and altered immune function, but the mechanisms underlying their immunotoxic effects remain incompletely understood. Because dendritic cells (DCs) play a central role in antigen presentation and initiation of adaptive immunity, this study investigated the effects of selected PFAS on DC maturation and the underlying molecular pathways. Human THP-1-derived DCs were exposed to four long chain PFAS followed by transcriptomic analysis, quantitative gene expression analysis, and pharmacological modulation of peroxisome proliferator-activated receptor alpha (PPARα)- and glucocorticoid receptor (GR)-associated pathways. Perfluorooctanoic acid (PFOA) induced the strongest transcriptional response, characterized by enrichment of pathways involved in fatty acid oxidation, peroxisomal metabolism, and PPAR signaling. Among the affected genes, pyruvate dehydrogenase kinase 4 (PDK4) emerged as a robust marker of PFAS-induced metabolic reprogramming. Functionally, PFAS exposure reduced expression of HLA-DR isotype, a key marker of DC maturation, with PFOA showing greater potency than the other compounds tested. Pharmacological inhibition experiments demonstrated that both PPARα-associated and GR-associated mechanisms contribute to the observed phenotype, although neither pathway alone fully accounted for the impairment. Overall, these findings indicate that PFAS disrupt DC maturation through coordinated immunometabolic reprogramming involving interconnected nuclear receptor signaling pathways, providing mechanistic support for the immunotoxic effects associated with PFAS exposure.