Omega-3 Polyunsaturated Fatty Acid Intervention Against Established Autoimmunity in a Murine Model of Toxicant-Triggered Lupus

Abstract

Workplace exposure to respirable crystalline silica dust (cSiO2) has been etiologically linked to the development of lupus and other human autoimmune diseases. Lupus triggering can be recapitulated in female NZBWF1 mice by four weekly intranasal instillations with 1 mg cSiO2. This elicits inflammatory/autoimmune gene expression and ectopic lymphoid structure (ELS) development in the lung within 1 week, ultimately driving early onset of systemic autoimmunity and glomerulonephritis. Intriguingly, dietary supplementation with docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid (PUFA) found in fish oil, beginning 2 week prior to cSiO2 challenge, prevented inflammation and autoimmune flaring in this novel model. However, it is not yet known how ω-3 PUFA intervention influences established autoimmunity in this murine model of toxicant-triggered lupus. Here we tested the hypothesis that DHA intervention after cSiO2-initiated intrapulmonary autoimmunity will suppress lupus progression in the NZBWF1 mouse. Six-week old NZWBF1 female mice were fed purified isocaloric diet for 2 weeks and then intranasally instilled with 1 mg cSiO2 or saline vehicle weekly for 4 consecutive weeks. One week after the final instillation, which marks onset of ELS formation, mice were fed diets supplemented with 0, 4, or 10 g/kg DHA. One cohort of mice (n = 8/group) was terminated 13 weeks after the last cSiO2 instillation and assessed for autoimmune hallmarks. A second cohort of mice (n = 8/group) remained on experimental diets and was monitored for proteinuria and moribund criteria to ascertain progression of glomerulonephritis and survival, respectively. DHA consumption dose-dependently increased ω-3 PUFA content in the plasma, lung, and kidney at the expense of the ω-6 PUFA arachidonic acid. Dietary intervention with high but not low DHA after cSiO2 treatment suppressed or delayed: (i) recruitment of T cells and B cells to the lung, (ii) development of pulmonary ELS, (iii) elevation of a wide spectrum of plasma autoantibodies associated with lupus and other autoimmune diseases, (iv) initiation and progression of glomerulonephritis, and (v) onset of the moribund state. Taken together, these preclinical findings suggest that DHA supplementation at a human caloric equivalent of 5 g/d was an effective therapeutic regimen for slowing progression of established autoimmunity triggered by the environmental toxicant cSiO2.

Centrality of Myeloid-Lineage Phagocytes in Particle-Triggered Inflammation and Autoimmunity

“…Additionally, DHA supplementation suppresses both cSiO 2 -induced autoantibody responses against a large number of SLE-associated autoantigens ( Rajasinghe et al, 2020 ) and cSiO 2 -triggered glomerulonephritis ( Bates et al, 2018 ). Lastly, we have recently demonstrated that DHA supplementation has value as a therapeutic intervention in this model ( Pestka et al, 2021 ). The demonstration that DHA acts at many stages of cSiO 2 -induced autoimmunity ( Figure 7 ) raises the possibility that ω-3 PUFA supplementation could be used as an intervention against other diseases associated with particle-triggered inflammation and autoimmunity.…”

Exposure to silicates and systemic autoimmune-related outcomes in rodents: a systematic review

“…Glomerulonephritis was also reported in crystalline silica-exposed DO mice [59]. These changes can eventually result in kidney nephritis and injury with significant proteinuria in both NZM 2410 and NZBWF1 mice [50,66,69].…”

“…A few papers used 4 instillations divided over 4 weeks, with a 1-week interval. C57BL/6 9 (36-38, 41, 42, 44-46, 67) 5 (54,55,62,63,68) NZM 2410 0 4 (21,47,49,50) NZWB/F1 0 9 (55,56,58,60,61,65,66,69) BXSB 0 2 (62,68) Other 0 5 (48,56,57,59,62) Rat 2 3…”

“…Moreover, the inflammatory response after crystalline silica exposure in the lungs of NZBWF1 mice is characterized by extensive perivascular and peri-bronchial lymphoplasmacytic infiltration consisting of IgG-producing plasma cells, and CD45R + B cells and CD3 + T lymphocytes [55,58,66]. The spatial architecture of these B and T cell aggregates resembles that of ectopic/ tertiary lymphoid tissue/structures (ELT/ELS).…”

Autoreactive B cells recruited to lungs by silica exposure contribute to local autoantibody production in autoimmune-prone BXSB and B cell receptor transgenic mice

“…In certain strains with aggressive lupus (i.e. NZM2410, NZBWF1, and New Zealand Black, or NZB, lupus mice), cSiO2 exposure increases ANA, anti-histone, anti-dsDNA, anti-ssDNA, and/or anti-RNP, Sm, Ro/SSA, and La/SSB Ig ( 19 – 28 ). In cSiO2-exposed female NZBWF1 mice, plasma assayed by an autoantigen protein microarray also revealed autoantibodies reactive with a diverse assortment of cytoplasmic, extracellular, and matrix proteins ( 27 , 28 ).…”