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Data from: Dietary docosahexaenoic acid supplementation inhibits acute pulmonary transcriptional and autoantibody responses to a single crystalline silica exposure in lupus-prone mice

Chauhan, Preeti1; Benninghoff, Abby2; Favor, Olivia1; Wagner, James1; Lewandowski, Ryan1; Rajasinghe, Lichchavi1; Harkema, Jack1; Pestka, James1

Published May 02, 2023; Updated Jan 27, 2024 on Dryad. https://doi.org/10.5061/dryad.5mkkwh79g

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Abstract

Short-term repeated intranasal exposure crystalline silica (cSiO2), a known human autoimmune trigger, induces uncontrolled inflammation, upregulated IFN-stimulated gene expression, diverse autoantibody production, and glomerulonephritis in lupus-prone female NZBWF1 mice. Dietary supplementation with the omega-3 fatty acid docosahexaenoic acid (DHA) prevents subchronic cSiO2 triggering of these lupus hallmarks. To understand how this intervention impacts acute effects of cSiO2, we fed NZBWF1 mice control (CON) or DHA-containing diet, subjected them to a single acute intranasal instillation of 2.5 mg cSiO2, then compared pulmonary inflammatory/autoimmune responses and autoimmune-related gene expression in experimental cohorts terminated at 7 and 28 d post-instillation (PI). Acute cSiO2 exposure of CON-fed mice elicited decreased macrophage and increased neutrophil numbers at 7 d PI, whereas at 28 d PI, CON-fed mice treated with particle displayed elevated total cell, macrophage, neutrophil, and lymphocyte counts. In contrast, DHA-fed mice treated with cSiO2 exhibited less macrophage loss at 7 d PI and reduced total cell, macrophage, and lymphocyte accumulation at 28 d PI. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) of lung sections suggested that cSiO2 induced more robust cell death at 7 d PI in CON-fed than DHA-fed mice. Targeted multiplex ELISA of lung extracts showed that at 28 d PI, cSiO2 induced higher concentrations of inflammation-associated cytokines (IL-1α, IL-6, and GM-CSF) and IFN-stimulated chemokines (CCL2, CCL3, CXCL10) in the CON-fed cohort than in the DHA-fed cohort. Autoantigen protein microarray of BALF collected at 28 d PI indicated that cSiO2 induced higher autoantibody responses for representative nuclear, ribosomal, mitochondrial, and complement proteins in CON-fed mice than DHA-fed mice. Gene expression analyses with NanoString Autoimmune Gene Expression assay revealed greater cSiO2-triggered upregulation of genes associated with TLR activation, DNA signaling, proinflammatory cytokines,  chemokines, type 1 and 2 IFN response signatures, lymphocyte trafficking, MHC class 1 antigen presentation, B and T cell activation at 7 and 28 d PI in CON-fed mice than those fed DHA. Ingenuity Pathway Analysis (IPA) further demonstrated that DHA supplementation quelled cSiO2-induced responses top upstream regulators of proinflammatory and IFN-regulated gene networks to observed in CON-fed mice. Altogether, this short-term model illustrated that DHA suppression of aberrant acute cSiO2-induced inflammation is linked to altered regulation of autoimmune-related gene expression in lupus-prone mice.