Nutritional Immunology and Inflammation
Intranasal instillation of lupus-prone mice with crystalline silica (cSiO2), a respirable particle linked to human lupus, mimics human lupus flaring by accelerating systemic autoimmunity and glomerulonephritis. Notably, these effects were prevented when mouse diets were supplemented with DHA. A broad-spectrum pathogenic autoantibodies (AAs) can be elicited relative to specificity and isotype during human lupus, each of which could differentially contribute to tissue injury. Here, we assessed how DHA influences the autoantibody spectrum over time in this novel preclinical model.
Female NZBWF1 mice at 6 weeks(wks) of age were fed isocaloric diets AIN-93G supplemented with DHA at 0, 4, or 10 g/kg diet, beginning either 2 wk before cSiO2 instillation (prevention) or 1 wk after cSiO2 instillation (treatment). For both groups, the mice were intranasally instilled with 1 mg cSiO2 or saline vehicle alone once per wk for 4 wks, starting at 8 wks of age. Cohorts were sacrificed 1, 5, 9, or 13 wks post-instillation (PI) of the last cSiO2 dose. Plasma was subjected to high-throughput AA profiling of different isotypes (IgG, IgM, IgA, and IgE) using a microarray containing 120 autoantigens.
cSiO2 triggered production of IgG AAs against components from the cell nucleus (nucleic acids and associated proteins), complement family, cytoplasm, membrane, and matrix proteins within 9 and 13 wk PI A supplementation before and after cSiO2 installation significantly inhibited the IgG AAs production. Importantly, known lupus markers such as anti-DNA, anti-RNP, anti-SM, anti-histone, anti-ds DNA, anti-Ro/SSA, and anti-La/SSB and anti-complement AAs, were inhibited with DHA. Spontaneous elevation of some IgG AAs in plasma, likely genome-driven, was evident at 13 wk in control groups compared to earlier time points. The prevention strategy with DHA showed a more robust effect compared to therapeutic strategy. The preventive effects of DHA treatment on IgM and IgA AAs also mimicked the effect on IgG at 13 wks.
Our results highlight a newly identified function of DHA in suppressing production of pathogenic AAs. The data provide preclinical proof of concept for the use of DHA supplementation as an adjunct to established therapeutics for preventing and treating the flaring of lupus and other autoimmune diseases.
Funding Sources : NIEHS grant, Lupus Foundation, and Dr. Robert and Carol Diebel Family Endowment.