Rapid Induction of Pulmonary Inflammation, Autoimmune Gene Expression, and Ectopic Lymphoid Neogenesis Following Acute Silica Exposure in Lupus-Prone Mice

• Published in: Frontiers in immunology Vol. 12; p. 635138
• Main Authors: Chauhan, Preeti S, Wagner, James G, Benninghoff, Abby D, Lewandowski, Ryan P, Favor, Olivia K, Wierenga, Kathryn A, Gilley, Kristen N, Ross, Elizabeth A, Harkema, Jack R, Pestka, James J
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 23.02.2021
• Subjects: Animals; autoimmune disease; Autoimmunity - genetics; B cell; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; chemokines; Chemotaxis, Leukocyte; crystalline silica; Cytokines - genetics; Cytokines - metabolism; Disease Models, Animal; Female; Gene Expression Regulation; Gene Regulatory Networks; Immunology; Inflammation Mediators - metabolism; Lung - immunology; Lung - metabolism; Lung - pathology; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lymphocyte Activation; Mice; Mice, Inbred NZB; Pneumonia - chemically induced; Pneumonia - genetics; Pneumonia - immunology; Pneumonia - metabolism; Silicon Dioxide; systemic lupus erythematosus; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tertiary Lymphoid Structures - immunology; Tertiary Lymphoid Structures - metabolism; Tertiary Lymphoid Structures - pathology; Time Factors; Transcriptome; type I interferon; type I interferon; B cell; systemic lupus erythematosus; T cell; crystalline silica; lung pathology; chemokines; autoimmune disease
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.635138

Occupational exposure to crystalline silica (cSiO ) is etiologically associated with systemic lupus erythematosus (lupus) and other autoimmune diseases. cSiO 's autoimmune effects in humans can be mimicked chronically in female lupus-prone NZBWF1 mice following repeated exposure to the particle. However, the immediate and short-term effects of cSiO in this widely used model of autoimmune disease are not well-understood. In the present study, we tested the hypothesis that a single acute cSiO dose triggers early presentation of cellular, histopathological, transcriptomic, and protein biomarkers of inflammation and autoimmunity in lupus-prone mice. Eight-week old female NZBWF1 mice were intranasally instilled once with 2.5 mg cSiO or saline vehicle and necropsied at 1, 7, 14, 21, and 28 d post-instillation (PI). Analyses of bronchoalveolar lavage fluid (BALF) and lung tissue revealed that by 7 d PI, acute cSiO exposure persistently provoked: (i) robust recruitment of macrophages, neutrophils, and lymphocytes into the alveoli, (ii) cell death as reflected by increased protein, double-stranded DNA, and lactate dehydrogenase activity, (iii) elevated secretion of the cytokines IL-1α, IL-1β, IL-18, TNF-α, IL-6, MCP-1, and B cell activation factor (BAFF), and (iv) upregulation of genes associated with chemokines, proinflammatory cytokines, lymphocyte activation, and type I interferon signaling. The appearance of these endpoints was subsequently followed by the emergence in the lung of organized CD3 T cells (14 d PI) and CD45R B cells (21 d PI) that were indicative of ectopic lymphoid structure (ELS) development. Taken together, acute cSiO exposure triggered a rapid onset of autoimmune disease pathogenesis that was heralded in the lung by unresolved inflammation and cell death, proinflammatory cytokine production, chemokine-driven recruitment of leukocytes, an interferon response signature, B and T cell activation, and ELS neogenesis. This short-term murine model provides valuable new insight into potential early mechanisms of cSiO -induced lupus flaring and, furthermore, offers a rapid venue for evaluating interventions against respirable particle-triggered inflammation and autoimmunity.