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 (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.
Highlights
Systemic lupus erythematosus is a devastating multi-organ autoimmune disease (AD) that adversely affects 1.5 million Americans, primarily women of child-bearing age [1]
Previous studies have shown that the Omega-3 Index, obtained by measuring docosahexaenoic acid (DHA) and EPA in total red blood cell (RBC) fatty acids, is correlated with the ω-3 polyunsaturated fatty acid (PUFA) content in other tissues [40,41,42]
Correlations between RBCs and tissues were higher for ω-3 and ω-6 PUFAs than for saturated fatty acid (SFA) and monounsaturated fatty acid (MUFA) (S1 Fig)
Summary
Systemic lupus erythematosus (lupus) is a devastating multi-organ autoimmune disease (AD) that adversely affects 1.5 million Americans, primarily women of child-bearing age [1]. While the genome is a primary predisposing factor for lupus, it is recognized that environmental exposures over a lifetime can exacerbate or ameliorate disease activity [2, 3]. The initiating step in lupus is loss of tolerance to nuclear self-antigens, resulting in production of autoreactive antibodies and formation of circulating immune complexes [1]. These complexes deposit in the tissues, where they promote activation and infiltration of circulating mononuclear cells leading to organ damage. In the kidney, this manifests as glomerulonephritis that, if left untreated, culminates in end-stage renal failure. Lupus patients typically experience quiescent periods with low disease activity intermittently interrupted by episodes of disease flaring marked by increased symptom severity and active organ damage [4]
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