Perfluorooctane sulfonate attenuates IgE/Ag-stimulated mast cell activation and anaphylactic responses via activating SHP-1 pathway.

Abstract

Perfluorooctane sulfonate (PFOS), a widely distributed and persistent organic pollutant, is known to cause immune dysfunction. In a previous study, we reported that PFOS modestly increases mast cell activation. However, its effects on FcεRI (a high-affinity IgE receptor)-mediated mast cell activation, a pivotal process in inflammatory allergic reactions and innate immunity, have not been clearly demonstrated. In this study, we investigated the effects of PFOS on IgE/Ag (antigen)-stimulated mast cell activation and the underlying mechanisms using bone marrow-derived mast cells (BMMCs) and a passive cutaneous anaphylaxis (PCA) mouse model. Oral administration of PFOS attenuated IgE/Ag-stimulated PCA responses. In the BMMCs model, PFOS reduced IgE/Ag-stimulated degranulation, intracellular Ca²⁺ levels, eicosanoid synthesis, and mRNA expression of pro-inflammatory cytokines. Consistently, PFOS decreased the phosphorylation of Syk and Lck, central tyrosine kinases in IgE/Ag-stimulated mast cell activation, along with their downstream signaling molecules (PLCγ1, AKT, and MAPKs), through the activation of tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1. Additionally, PFOS reduced the phosphorylation of FcεRI-associated tyrosine kinases Fyn and Lyn. Fluorine-19 nuclear magnetic resonance spectroscopy revealed reduced fluorine signals of PFOS upon interaction with the plasma membrane, suggesting that PFOS accumulates in plasma membranes and interferes with FcεRI signaling by acting upstream, close to the membrane. Moreover, PFOS attenuated lipopolysaccharide-stimulated mRNA expression of TNFα and IL-6. In conclusion, PFOS exposure disrupts FcεRI-mediated allergic responses and modulates innate immune responses.