Influence of Total Western Diet on Docosahexaenoic Acid Suppression of Silica-Triggered Lupus Flaring in NZBWF1 Mice

Authors

Kristen N. Gilley, Michigan State University
Kathryn A. Wierenga, Michigan State University
Preeti S. Chauhaun, Michigan State University
James G. Wagner, Michigan State University
Ryan P. Lewandowski, Michigan State University
Elizbeth A. Ross, Michigan State University
A. L. Lock, Michigan State University
Jack R. Harkema, Michigan State University
Abby D. Benninghoff, Utah State UniversityFollow
James J. Pestka, Michigan State University

Document Type

Article

Journal/Book Title/Conference

PL o S One

Volume

15

Issue

5

Publisher

Public Library of Science

Publication Date

5-15-2020

First Page

1

Last Page

27

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

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 50^th 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.

Recommended Citation

Gilley KN, Wierenga KA, Chauhuan PS, Wagner JG, Lewandowski RP, Ross EA, et al. (2020) Influence of total western diet on docosahexaenoic acid suppression of silica-triggered lupus flaring in NZBWF1 mice. PLoS ONE 15(5): e0233183. https://doi.org/10.1371/journal.pone.0233183