Autoimmune diseases are chronic, uncured, life-altering illnesses caused by immune cells mistakenly attacking and damaging host tissues. While genetic predispositions play a vital role in the onset and development of autoimmune disease, exposure to environmental toxicants such as bacterial lipopolysaccharide (LPS) and respirable crystalline silica (cSiO2) has also been etiologically implicated in autoimmune pathogenesis and progression. Current mainstay drugs for managing autoimmune disease symptoms (e.g., glucocorticoids, monoclonal antibodies) effectively reduce inflammation and associated tissue damage but also burden patients with adverse side effects and steep financial costs from long-term use. Intriguingly, preclinical and clinical studies suggest that two lipidome-modifying agents, dietary ω-3 polyunsaturated fatty acids (PUFAs) and small molecule inhibitors of soluble epoxide hydrolase (sEH), may improve disease status in systemic autoimmune diseases, including lupus. Previous studies conducted in our laboratory suggest that the ω-3 PUFA docosahexaenoic acid (DHA) abrogates cSiO2-triggered autoimmune responses when given at realistic human equivalent doses to female lupus-prone NZBWF1 mice and suppresses LPS-induced expression of proinflammatory mediators at physiologically relevant concentrations in several macrophage models. In addition, the sEH inhibitor 1-trifluoromethoxyphenul-3-(1-propionylpiperidin-4-yl)urea (TPPU) delays the onset of genetically driven glomerulonephritis (GN) and prolongs lifespan in NZBWF1 mice with excellent pharmacokinetic properties. In this dissertation, I sought to build upon these findings by testing the overarching hypothesis that modulating the cellular lipidome delays initiation and progression of environmentally-triggered autoimmunity. Three research aims were pursued to test my hypothesis. In the first aim, we utilized a previously reported in vivo model of LPS-accelerated (GN) in NZBWF1 mice to compare the impacts of rough and smooth LPS chemotypes on GN onset and to subsequently evaluate the effects of DHA and/or sEH inhibition on disease development. Rough LPS elicited severe GN while smooth LPS did not. Additionally, DHA and sEH inhibition separately ameliorated LPS-accelerated GN, but therapeutic effects were diminished upon combining the treatments. In the second aim, we employed a novel in vitro alveolar macrophage surrogate model—the fetal liver-derived alveolar macrophage (FLAM)—to query the impacts of LPS, cSiO2, and DHA on a broad oxylipin panel consisting of 156 metabolites, as well as proinflammatory cytokine release, lysosomal membrane permeabilization (LMP), mitochondrial toxicity, and cell death. cSiO2 evoked marked biosynthesis of ω-6 PUFA metabolites in vehicle-treated cells, while DHA significantly skewed the cellular lipidome toward ω-3 PUFA metabolites following cSiO2 exposure. DHA also suppressed cSiO2-induced proinflammatory cytokine release but did not affect LMP, mitochondrial toxicity, or cell death. In the third aim, we used a novel in vivo model of acute cSiO2-triggered lupus flaring in NZBWF1 mice to assess the impacts of sEH inhibition on lung inflammation and early autoimmunity. sEH inhibition reduced neutrophil and monocyte numbers in lung lavage fluid but did not improve cSiO2-induced centriacinar inflammation and fibrosis, perivascular ectopic lymphoid tissue neogenesis, T and B lymphocyte infiltration into the lung, secretion of antinuclear antibodies into lavage fluid and plasma, or gene expression and production of proinflammatory mediators in the lung. Taken together, the studies presented in this dissertation provide valuable insight into how lipidome-modulating interventions (e.g., ω-3 PUFAs and sEH inhibitors) may impact the initiation and development of environmentally-triggered autoimmune diseases such as lupus. Furthermore, this dissertation highlights several novel preclinical models that can be used in future in vitro and in vivo screening of lipidome-modulating agents against environmentally-triggered autoimmunity.
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