Silica-mediated exacerbation of inflammatory arthritis: A novel murine model

Abstract

ObjectiveThe mucosal origin hypothesis in rheumatoid arthritis (RA) posits that inhalant exposures, such as cigarette smoke and crystalline silica (c-silica), trigger immune responses contributing to disease onset. Despite the established risk posed by these exposures, the mechanistic link between inhalants, lung inflammation, and inflammatory arthritis remains poorly understood, partly from the lack of a suitable experimental model. As c-silica accelerates autoimmune phenotypes in lupus models and is a recognized risk factor for several autoimmune diseases, we investigated whether c-silica exposure could induce RA-like inflammatory arthritis in mice. MethodsTwo arthritis-prone mouse strains, BXD2/TyJ and HLA-DR4 transgenic (DR4-Tg), were exposed to c-silica or PBS via oropharyngeal instillation. Arthritis was evaluated by clinical signs and histopathology. Autoimmunity was further evaluated by serological analysis, including autoantibodies and cytokines and chemokines. Lung pathology was evaluated by histopathology and immunofluorescent staining for lymphocyte and macrophages. ResultsC-silica exposure induced chronic pulmonary silicosis in all mice. In BXD2 mice, this was associated with rapid arthritis development, marked by synovitis, bone erosion, and elevated serum autoantibody levels targeting various antigens, including snRNP and citrullinated protein. Additionally, BXD2 mice exhibited inducible bronchus-associated lymphoid tissue (iBALT) formation and elevated autoantibodies in bronchoalveolar lavage fluid (BALF). Conversely, DR4-Tg mice had no significant arthritis, negligible autoantibody responses, and milder lung inflammation lacking iBALT. ConclusionWe introduce a novel model of c-silica-mediated inflammatory arthritis, creating a novel platform to unravel the molecular and cellular underpinnings of RA and advance understanding of the mucosal origin hypothesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/631488v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@88080aorg.highwire.dtl.DTLVardef@c7d935org.highwire.dtl.DTLVardef@8548d3org.highwire.dtl.DTLVardef@703ceb_HPS_FORMAT_FIGEXP M_FIG C_FIG