Silica, Silicosis, and Autoimmunity

Abstract

Inhalation of dust containing crystalline silica is associated with a number of acute and chronic diseases including systemic autoimmune diseases. Evidence for the link with autoimmune disease comes from epidemiological studies linking occupational exposure to crystalline silica dust with the systemic autoimmune diseases systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Although little is known regarding the mechanism by which silica exposure leads to systemic autoimmune disease, there is a voluminous literature on silica exposure and silicosis that may help identify immune processes that precede development of autoimmunity. The pathophysiology of silicosis consists of deposition of silica particles in the alveoli of the lung. Ingestion of these particles by macrophages initiates an inflammatory response, which stimulates fibroblasts to proliferate and produce collagen. Silica particles are encased by collagen leading to fibrosis and the nodular lesions characteristic of the disease. The steps in the development of silicosis, including acute and chronic inflammation and fibrosis, have different molecular and cellular requirements, suggesting that silica-induced inflammation and fibrosis may be mechanistically separate. Significantly, it is unclear whether silica-induced inflammation and fibrosis contribute similarly to the development of autoimmunity. Nonetheless, the findings from human and animal model studies are consistent with an autoimmune pathogenesis that begins with activation of the innate immune system leading to proinflammatory cytokine production, pulmonary inflammation leading to activation of adaptive immunity, breaking of tolerance, and autoantibodies and tissue damage. The variable frequency of these immunological features following silica exposure suggests substantial genetic involvement and gene/environment interaction in silica-induced autoimmunity. However, numerous questions remain unanswered.

Keywords: animal model; autoimmunity; human; silica; silicosis.

Figure 1

Silica-induced activation of inflammasome and IL-1 production. IL-1α, released from alveolar macrophages following crystalline exposure, results in NF-κB activation and transcription and translation of pro-IL-1β. Phagocytosis of crystalline silica leads to phagosomal damage and release of phagosome contents into the cytoplasm. This results in the activation of NALP3 and its association with the intracellular adapter protein ASC, which combines with and activates pro-caspase-1. The resulting inflammasome cleaves pro-IL-1β to the proinflammatory IL-1β. However, binding of immobilized silica crystals to the cell membrane of macrophages is also sufficient to induce IL-1β without evidence of lysosomal damage. Activation of the NALP3 inflammasome by silica also results in efflux of intracellular potassium ions, suggesting a possible interaction of silica with a membrane-associated protein, but it is unclear if K⁺ efflux following binding of immobilized silica crystals to the cell membrane results in inflammasome activation. Scavenger receptors have a role in the recognition and uptake of silica. NALP3, NACHT, LRR, and PYD domains-containing protein 3; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; NF-κB, nuclear factor-κB; IL, interleukin.

Figure 2

Molecular and cellular components involved in silica-induced inflammation and fibrosis. Silicosis is marked by inflammation and fibrosis with the formation of nodular lesions in the upper lobes of the lungs. The collagen containing silicotic nodules are a specific response to crystalline silica. However, the cellular and molecular components responsible for the inflammatory and fibrotic responses are not the same. Components required for inflammation (acute or chronic) and fibrosis are highlighted in red, while those not essential have been highlighted in green (see text for details). TNF, tumor necrosis factor; IFN, interferon; MyD88, myeloid differentiation primary response gene 88; IL, interleukin; NK, natural killer; NKT, natural killer T cell; IRF, interferon regulatory factor; TGF, transforming growth factor.