Omega-3 fatty acid intake suppresses induction of diverse autoantibody repertoire by crystalline silica in lupus-prone mice

• Published in: Autoimmunity (Chur, Switzerland) Vol. 53; no. 7; pp. 415 - 433
• Main Authors: Rajasinghe, Lichchavi D., Li, Quan-Zhen, Zhu, Chengsong, Yan, Mei, Chauhan, Preeti S., Wierenga, Kathryn A., Bates, Melissa A., Harkema, Jack R., Benninghoff, Abby D., Pestka, James J.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02.10.2020; Taylor & Francis Group
• Subjects: Animals; antigens; autoantibodies; Autoantibodies - immunology; autoantibody; autoantigen; Autoantigens - immunology; Autoimmune Diseases - etiology; autoimmune hepatitis; Autoimmunity; biomarkers; breathing; celiac disease; cell death; collagen; complement; diet; Dietary Fats; Disease Models, Animal; DNA; docosahexaenoic acid; erythrocytes; Fatty Acids, Omega-3 - metabolism; fibrinogen; fibronectins; gene expression; glomerulonephritis; histones; humans; IgA; IgG; IgM; Immunoglobulin Isotypes - immunology; inflammation; lungs; Lupus Erythematosus, Systemic - etiology; Mice; microarray technology; myositis; necrosis; Occupational Diseases - etiology; Occupational Exposure; omega-3 fatty acids; phospholipids; rheumatoid arthritis; ribonucleoproteins; sclerosis; silica; Silicon Dioxide - adverse effects; systemic lupus erythematosus; vasculitis; vimentin; working conditions; ω-3 Polyunsaturated fatty acids; IgA; systemic lupus erythematosus; autoantibody; autoimmunity; docosahexaenoic acid; silica; ω-3 Polyunsaturated fatty acids; IgG; autoantigen; IgM
• ISSN: 0891-6934; 1607-842X; 1607-842X
• DOI: 10.1080/08916934.2020.1801651

Inhalation of crystalline silica (cSiO 2 ) in the workplace is etiologically linked to lupus and other autoimmune diseases. Exposing lupus-prone NZBWF1 mice to respirable cSiO 2 unleashes a vicious cycle of inflammation and cell death in the lung that triggers interferon-regulated gene expression, ectopic lymphoid structure (ELS) development, elevation of local and systemic autoantibodies (AAbs), and glomerulonephritis. However, cSiO 2 -induced inflammation and onset of autoimmunity can be prevented by inclusion of the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) into the diet of these mice. Since cSiO 2 both causes cell death and interferes with efferocytosis, secondary necrosis of residual cell corpses might provide a rich and varied autoantigen (AAg) source in the lung. While it is known that the particle induces anti-nuclear and anti-dsDNA AAbs in NZBWF1 mice, the full extent of the cSiO 2 -induced AAb response relative to specificity and isotype is not yet understood. The purpose of this study was to test the hypotheses that cSiO 2 exposure induces a wide spectrum of AAbs in the pulmonary and systemic compartments, and that dietary DHA intervention prevents these changes. Archived tissue fluid samples were obtained from a prior study in which NZBWF1 mice were fed purified isocaloric diets containing no DHA (control) or DHA corresponding calorically to human doses of 2 and 5 g/day. Mice were intranasally instilled with 1 mg cSiO 2 or saline vehicle weekly for 4 weeks, then groups euthanized 1, 5, 9, or 13 weeks post-instillation (PI) of the last cSiO 2 dose. Bronchoalveolar lavage fluid (BALF) and plasma from each time point were subjected to AAb profiling using a microarray containing 122 AAgs. cSiO 2 triggered robust IgG and IgM AAb responses against lupus-associated AAgs, including DNA, histones, ribonucleoprotein, Smith antigen, Ro/SSA, La/SSB, and complement as early as 1 week PI in BALF and 5 weeks PI in plasma, peaking at 9 and 13 weeks PI, respectively. Importantly, cSiO 2 also induced AAbs to AAgs associated with rheumatoid arthritis (collagen II, fibrinogen IV, fibrinogen S, fibronectin, and vimentin), Sjögren's syndrome (α-fodrin), systemic sclerosis (topoisomerase I), vasculitis (MPO and PR3), myositis (Mi-2, TIF1-γ, MDA5), autoimmune hepatitis (LC-1), and celiac disease (TTG). cSiO 2 elicited comparable but more modest IgA AAb responses in BALF and plasma. cSiO 2 -induced AAb production was strongly associated with time dependent inflammatory/autoimmune gene expression, ELS development, and glomerulonephritis. AAb responses were dose-dependently suppressed by DHA supplementation and negatively correlated with the ω-3 index, an erythrocyte biomarker of ω-3 content in tissue phospholipids. Taken together, these findings suggest that cSiO 2 exposure elicits a diverse multi-isotype repertoire of AAbs, many of which have been reported in individuals with lupus and other autoimmune diseases. Furthermore, induction of this broad AAb spectrum could be impeded by increasing ω-3 tissue content via dietary DHA supplementation.