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

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

Published In Front Immunol, (2021)

Abstract: Occupational exposure to crystalline silica (cSiO2) is etiologically associated with systemic lupus erythematosus (lupus) and other autoimmune diseases. cSiO2'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 cSiO2 in this widely used model of autoimmune disease are not well-understood. In the present study, we tested the hypothesis that a single acute cSiO2 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 cSiO2 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 cSiO2 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 cSiO2 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 cSiO2-induced lupus flaring and, furthermore, offers a rapid venue for evaluating interventions against respirable particle-triggered inflammation and autoimmunity.

PubMed ID: 33732257

MeSH Terms: Animals; Autoimmunity*/genetics; B-Lymphocytes/immunology; B-Lymphocytes/metabolism; Chemotaxis, Leukocyte; Cytokines/genetics; Cytokines/metabolism*; Disease Models, Animal; Female; Gene Expression Regulation; Gene Regulatory Networks; 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; T-Lymphocytes/immunology; T-Lymphocytes/metabolism; Tertiary Lymphoid Structures/immunology*; Tertiary Lymphoid Structures/metabolism; Tertiary Lymphoid Structures/pathology; Time Factors; Transcriptome