Silica exposure as a driver of inflammatory arthritis: insights from genetically susceptible mouse models 3289

Abstract Description Occupational exposure to silica is strongly associated with rheumatoid arthritis (RA), but causality remains unproven. To bridge this gap, we investigated whether pulmonary silicosis could induce RA-like arthritis in a mouse model. BXD2 mice that develop autoimmune arthritis and six Collaborative Cross (CC) strains not known to develop arthritis were exposed trans-orally to silica (5 mg) or PBS and then studied at 12 and 20 weeks. Arthritis, silicosis, and kidney disease were assessed by histology. Serum IgG, autoAb, and cytokine levels were examined. Silica exposure markedly exacerbated arthritis in BXD2 mice and induced arthritis in one CC (039) strain. In both, arthritis emerged as early as 12 weeks post-exposure and was severe by 20 weeks. Mild arthritis was seen in some PBS-exposed BXD2 mice at 20 weeks but none in CC039. Both strains had elevated Abs to nuclei, citrullinated protein, and Sm/RNP, along with prominent lung silicosis, fibrosis, and ectopic lymphoid structures. CC039 also developed unique silica-containing necrotic nodules and granulomas. Arthritis-resistant CC strains had less lung inflammation and lymphoid accumulations.Thus, we show that silica exposure can drive inflammatory arthritis in genetically predisposed mice. This establishes compelling models to unravel the mechanistic link between mucosal inflammation and RA and underscores the critical interplay between environmental triggers and genetic susceptibility in autoimmune pathogenesis. Topic Categories Basic Autoimmunity (BA)