Sinus mast cell accumulation and persistence suggest a unique endotype in toxin exposure-associated chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is more prevalent and severe in military Veterans with deployment-related environmental toxin exposures. The mechanisms driving this aggressive phenotype are poorly understood, and the role of mast cells remains understudied. We sought to characterize the immunophenotype of toxin-associated CRS and develop a preclinical model to investigate disease persistence. We identified a significant and selective expansion of sinus mast cells in Veterans with deployment-related exposures compared to unexposed controls, an effect most prominent in patients without nasal polyps. RNA sequencing of sinus tissue from exposed patients confirmed the upregulation of mast cell activation pathways. We also developed a murine model in which co-exposure to burn pit constituents (BPC) and an aeroallergen synergistically exacerbated sinonasal inflammation. Strikingly, mast cell accumulation persisted and continued to increase for weeks after toxin exposure ceased, a phenomenon not observed in mice challenged with allergen alone. Our findings reveal a novel mast cell-driven phenotype in toxin exposure-associated CRS. The persistent accumulation of mast cells in our preclinical model provides a potential mechanism for the chronicity of sinonasal symptoms following xenobiotic exposures, identifying mast cells as a potential therapeutic target for this emerging CRS phenotype.