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

Abstract

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 (cSiO 2), 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. cSiO 2-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 50 th percentile U.S. macronutrient distribution to discern how DHA supplementation and/or SFA and ω-6 reduction influences cSiO 2-triggered lupus flaring in female NZBWF1 mice. Six-week-old mice were fed isocaloric experimental diets for 2 wks, intranasally instilled with cSiO 2 or saline vehicle weekly for 4 wks, and tissues assessed for lupus endpoints 11 wks following cSiO 2 instillation. In mice fed basal mTWD, cSiO 2 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

Requisite Omega-3 HUFA Biomarker Thresholds for Preventing Murine Lupus Flaring

“…Data used for this study were collected from our previously published investigations based on three DHA feeding studies (35)(36)(37)(38) (see Supplementary Data). Each study used female NZBWF1 mice obtained from Jackson Laboratories (Bar Harbor, ME).…”

“…Elevated IRG expression is highly associated with flaring and increased disease severity in lupus (43). It was demonstrated in Studies 2 and 3 that IRG expression is upregulated in cSiO 2exposed NZBWF1 mice and that this is suppressed by DHA supplementation (35,38). Here, an IFN score was generated…”

“…High unsaturated fatty acid (HUFA) score increases with DHA intake in NZBWF1 mice and can be predicted based on diet composition in cSiO 2 -treated NZBWF1 mice. Animals were fed different diets for Studies 1 (HF AIN-93G), 2 (AIN-93G), and 3 (MTWD and MTWD ↓SF.ω6) with or without DHA (see Table 1 by combining the autoscaled expression of 12 IRGs measured in animals fed AIN-93G, MTWD, and MTWD ↓SF.ω6 (38). Resultant IFN scores negatively correlated with ω-3 HUFA scores (R 2 = 0.29, p < 0.0001, Figure 3A).…”

“…Higher RBC ω-3 HUFA Scores Correspond to Reduced Pro-inflammatory Cytokines and Leukocyte Infiltration in BALF Intranasal instillation of cSiO 2 elicits local sterile inflammation in the lungs of NZBWF1 mice that is associated with elevated proinflammatory cytokines, chemokines, and mononuclear cell influx, all of which can be suppressed by DHA supplementation (36)(37)(38). Here it was found that IL-6 (R 2 = 0.26, p = 0.0001, Figure 4A), MCP-1 (R 2 = 0.29, p < 0.0001, Figure 4B), and TNFα (R 2 = 0.39, p < 0.0001, Figure 4C) concentrations in the BALF were negatively correlated with the ω-3 HUFA score.…”

“…The goal of the present study was to test the hypothesis that the ω-3 HUFA score and the O3I inversely correlate with indicators of inflammation and autoimmune pathogenesis during cSiO 2 -triggered lupus flaring in NZBWF1 mice. Data used to test this hypothesis were drawn from three unique DHA supplementation studies recently published by our laboratory (36)(37)(38) that employed both purified mouse diets, as well as more complex diets reflecting Western eating patterns. Our findings indicate that increases in both the O3I and the ω-3 HUFA score were strongly associated with suppression of autoimmune pathogenesis in this preclinical mouse model of toxicant-triggered lupus flaring.…”