title: Silica-Triggered Autoimmunity in Lupus-Prone Mice Blocked by Docosahexaenoic Acid Consumption.
abstract: Occupational exposure to respirable crystalline silica (cSiO2, quartz) is etiologically linked to systemic lupus erythematosus (lupus) and other human autoimmune diseases (ADs). In the female NZBWF1 mouse, a widely used animal model that is genetically prone to lupus, short-term repeated intranasal exposure to cSiO2 triggers premature initiation of autoimmune responses in the lungs and kidneys. In contrast to cSiO2's triggering action, consumption of the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) prevents spontaneous onset of autoimmunity in this mouse strain. The aim of this study was to test the hypothesis that consumption of DHA will prevent cSiO2-triggered autoimmunity in the female NZBWF1 mouse. Mice (6 wk old) were fed isocaloric AIN-93G diets containing 0.0, 0.4, 1.2 or 2.4% DHA. Two wk after initiating feeding, mice were intranasally instilled with 1 mg cSiO2 once per wk for 4 wk and maintained on experimental diets for an additional 12 wk. Mice were then sacrificed and the lung, blood and kidney assessed for markers of inflammation and autoimmunity. DHA was incorporated into lung, red blood cells and kidney from diet in a concentration-dependent fashion. Dietary DHA dose-dependently suppressed cSiO2-triggered perivascular leukocyte infiltration and ectopic lymphoid tissue neogenesis in the lung. DHA consumption concurrently inhibited cSiO2-driven elevation of proinflammatory cytokines, B-cell proliferation factors, IgG and anti-dsDNA Ig in both bronchoalveolar lavage fluid and plasma. DHA's prophylactic effects were further mirrored in reduced proteinuria and glomerulonephritis in cSiO2-treated mice. Taken together, these results reveal that DHA consumption suppresses cSiO2 triggering of autoimmunity in female NZBWF1 mice as manifested in the lung, blood and kidney. Our findings provide novel insight into how dietary modulation of the lipidome might be used to prevent or delay triggering of AD by cSiO2. Such knowledge opens the possibility of developing practical, low-cost preventative strategies to reduce the risk of initiating AD and subsequent flaring in cSiO2-exposed individuals. Additional research in this model is required to establish the mechanisms by which DHA suppresses cSiO2-induced autoimmunity and to ascertain unique lipidome signatures predictive of susceptibility to cSiO2-triggered AD.
authors: Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, 48824, United States of America.|Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824, United States of America.
authors: Melissa A
authors: MA
authors: Bates
authors: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, 30625, Germany.
authors: Christina
authors: C
authors: Brandenberger
authors: Department of Pathobiological Studies, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, 70803, United States of America.
authors: Ingeborg I
authors: II
authors: Langohr
authors: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, 48824, United States of America.
authors: Kazuyoshi
authors: K
authors: Kumagai
authors: Department of Animal Science, Michigan State University, East Lansing, MI, 48824, United States of America.
authors: Adam L
authors: AL
authors: Lock
authors: Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824, United States of America.|Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, 48824, United States of America.
authors: Jack R
authors: JR
authors: Harkema
authors: Center for Environmental Health Sciences, University of Montana, Missoula, MT, 59812, United States of America.
authors: Andrij
authors: A
authors: Holian
authors: Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, 48824, United States of America.|Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824, United States of America.
authors: James J
authors: JJ
authors: Pestka
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D007111:Immunity, Cellular; D007668:Kidney / Q000187:drug effects; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008962:Models, Theoretical; D016273:Occupational Exposure / Q000009:adverse effects; D012822:Silicon Dioxide / Q000276:immunology*
chemical_list: D004281:Docosahexaenoic Acids; D012822:Silicon Dioxide