Silicosis and Silica-Induced Autoimmunity in the Diversity Outbred Mouse

Abstract

Epidemiological studies have confidently linked occupational crystalline silica exposure to autoimmunity, but pathogenic mechanisms and role of genetic predisposition remain poorly defined. Although studies of single inbred strains have yielded insights, understanding the relationships between lung pathology, silica-induced autoimmunity, and genetic predisposition will require examination of a broad spectrum of responses and susceptibilities. We defined the characteristics of silicosis and autoimmunity and their relationships using the genetically heterogeneous diversity outbred (DO) mouse population and determined the suitability of this model for investigating silica-induced autoimmunity. Clinically relevant lung and autoimmune phenotypes were assessed 12 weeks after a transoral dose of 0, 5, or 10 mg crystalline silica in large cohorts of DO mice. Data were further analyzed for correlations, hierarchical clustering, and sex effects. DO mice exhibited a wide range of responses to silica, including mild to severe silicosis and importantly silica-induced systemic autoimmunity. Strikingly, about half of PBS controls were anti-nuclear antibodies (ANA) positive, however, few had disease-associated specificities, whereas most ANAs in silica-exposed mice showed anti-ENA5 reactivity. Correlation and hierarchical clustering showed close association of silicosis, lung biomarkers, and anti-ENA5, while other autoimmune characteristics, such as ANA and glomerulonephritis, clustered separately. Silica-exposed males had more lung inflammation, bronchoalveolar lavage fluid cells, IL-6, and autoantibodies. DO mice are susceptible to both silicosis and silica-induced autoimmunity and show substantial individual variations reflecting their genetic diverseness and the importance of predisposition particularly for autoimmunity. This model provides a new tool for deciphering the relationship between silica exposure, genes, and disease.

Crystalline Silica Impairs Efferocytosis Abilities of Human and Mouse Macrophages: Implication for Silica-Associated Systemic Sclerosis

“…The concentration of SiO 2 in human MDM (25 µg/cm 2 ) was similar to previous studies evaluating the impact of SiO 2 on alveolar M (40). The concentration of SiO 2 used in vivo (1.5 mg/mice), although lower than the concentrations used in mouse models of silicosis (2.5 to 10 mg/mice) (41)(42)(43), was able to induce granuloma formation (data not shown). We can thus hypothesize that the observed defect of efferocytosis at 1.5 mg/mice may also occur with higher concentrations of SiO 2 .…”

“…Indeed, in mouse models of SLE, ROCK1/2 are spontaneously up-regulated and Y27632 significantly reduces serum levels of pro-inflammatory cytokines. Efferocytosis and activation of RhoA/ROCK could represent a key pathogenic process at the crossroads of systemic autoimmunity, M and silica exposure: in mouse models of SLE, SiO 2 inhalation is associated with more severe visceral manifestations of the disease and higher levels of ANA (43,49,50). ANA produced after SiO 2 exposure specifically target apoptotic cells (51) and an altered efferocytosis after SiO 2 inhalation could lead to an excess of uncleared apoptotic cells with subsequent increased production of these ANA.…”

The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection

“…Examples include similarities between mice and people in IFN-␥ pathways that are important in human MSMD syndrome immu-nodeficiencies (33) and in the roles of type 1 interferons and neutrophils in disease progression (11,49). Studies using DO mice have already advanced the discovery of genes involved in autoimmune silicosis (50), in a wide range of immunological features (51), and in viral infections (52). To date, this resource has not been much used in bacterial infections.…”

Relevance of Essential Trace Elements in Nutrition and Drinking Water for Human Health and Autoimmune Disease Risk

“…In vivo studies have shown lipid peroxidation, oxidative stress, an increase in IgM, serum IgG and the presence of ANA in mice exposed to silica, supporting its role as an adjuvant of T lymphocytes and as a possible factor triggering autoimmune diseases such as SLE and glomerulonephritis [97].…”