Influence of total western diet on docosahexaenoic acid suppression of silica-triggered lupus flaring in NZBWF1 mice

• Published in: PloS one Vol. 15; no. 5; p. e0233183
• Main Authors: Gilley, Kristen N, Wierenga, Kathryn A, Chauhuan, Preeti S, Wagner, James G, Lewandowski, Ryan P, Ross, Elizbeth A, Lock, A L, Harkema, Jack R, Benninghoff, Abby D, Pestka, James J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.05.2020; Public Library of Science (PLoS)
• Subjects: Animals; Antibodies; Apoptosis; Autoantibodies; Autoimmune diseases; Autoimmunity; B-Lymphocytes - immunology; Biochemistry; Biological response modifiers; Biology and Life Sciences; Chemokines; Cytokines; Cytokines - metabolism; Diet; Diet therapy; Diet, Western - adverse effects; Dietary Supplements; Disease Models, Animal; Diseases; Docosahexaenoic acid; Docosahexaenoic Acids - pharmacology; Fatty acids; Fatty Acids - pharmacology; Fatty Acids, Omega-3 - metabolism; Fatty Acids, Omega-3 - pharmacology; Fatty Acids, Omega-6 - metabolism; Fatty Acids, Omega-6 - pharmacology; Female; Females; Food science; Gene expression; Genes; Genomes; Glomerulonephritis; Glomerulonephritis - diet therapy; Glomerulonephritis - metabolism; Glomerulonephritis - pathology; Health; Health aspects; Inflammation; Inflammation - immunology; Interferon; Interferon-gamma - metabolism; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidneys; Leukocytes; Lung - metabolism; Lung - pathology; Lungs; Lupus; Lupus Erythematosus, Systemic - chemically induced; Lupus Erythematosus, Systemic - diet therapy; Medicine and Health Sciences; Mice; Molecular biology; Nephritis; Nutrition; Omega 3 fatty acids; Omega 6 fatty acids; Polyunsaturated fatty acids; Remission; Research and Analysis Methods; Silica; Silicon dioxide; Silicon Dioxide - toxicity; Systemic lupus erythematosus; T-Lymphocytes - immunology; Toxicology; Unsaturated fatty acids; Veterinary medicine; Women; United States; East Lansing Michigan; United States > US; Utah; Michigan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0233183

Lupus is a debilitating multi-organ autoimmune disease clinically typified by periods of flare and remission. Exposing lupus-prone female NZBWF1 mice to crystalline silica (cSiO2), a known human autoimmune trigger, mimics flaring by inducing interferon-related gene (IRG) expression, inflammation, ectopic lymphoid structure (ELS) development, and autoantibody production in the lung that collectively accelerate glomerulonephritis. cSiO2-triggered flaring in this model can be prevented by supplementing mouse diet with the ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA). A limitation of previous studies was the use of purified diet that, although optimized for rodent health, does not reflect the high American intake of saturated fatty acid (SFA), ω-6 PUFAs, and total fat. To address this, we employed here a modified Total Western Diet (mTWD) emulating the 50th percentile U.S. macronutrient distribution to discern how DHA supplementation and/or SFA and ω-6 reduction influences cSiO2-triggered lupus flaring in female NZBWF1 mice. Six-week-old mice were fed isocaloric experimental diets for 2 wks, intranasally instilled with cSiO2 or saline vehicle weekly for 4 wks, and tissues assessed for lupus endpoints 11 wks following cSiO2 instillation. In mice fed basal mTWD, cSiO2 induced robust IRG expression, proinflammatory cytokine and chemokine elevation, leukocyte infiltration, ELS neogenesis, and autoantibody production in the lung, as well as early kidney nephritis onset compared to vehicle-treated mice fed mTWD. Consumption of mTWD containing DHA at the caloric equivalent to a human dose of 5 g/day dramatically suppressed induction of all lupus-associated endpoints. While decreasing SFA and ω-6 in mTWD modestly inhibited some disease markers, DHA addition to this diet was required for maximal protection against lupus development. Taken together, DHA supplementation at a translationally relevant dose was highly effective in preventing cSiO2-triggered lupus flaring in NZBWF1 mice, even against the background of a typical Western diet.