Requisite Omega-3 HUFA Biomarker Thresholds for Preventing Murine Lupus Flaring

Abstract

Lupus is a systemic autoimmune disease typified by uncontrolled inflammation, disruption of immune tolerance, and intermittent flaring – events triggerable by environmental factors. Preclinical and clinical studies reveal that consumption of the marine ω-3 highly unsaturated fatty acids (HUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) might be used as a precision nutrition intervention to lessen lupus symptoms. The anti-inflammatory and pro-resolving effects of ω-3 HUFAs are inextricably linked to their presence in membrane phospholipids. The ω-3 HUFA score, calculated as [100 × (ω-3 HUFAs/(ω-3 HUFAs + ω-6 HUFAs))] in red blood cells (RBCs), and the Omega-3 Index (O3I), calculated as [100 × ((DHA+EPA)/total fatty acids)] in RBCs, are two biomarkers potentially amenable to relating tissue HUFA balance to clinical outcomes in individuals with lupus. Using data from three prior preclinical DHA supplementation studies, we tested the hypothesis that the ω-3 HUFA score and the O3I inversely correlate with indicators of autoimmune pathogenesis in the cSiO 2 -triggered lupus flaring model. The three studies employed both low and high fat rodent diets, as well as more complex diets emulating the U.S. dietary pattern. The ω-3 HUFA scores in RBCs were comparatively more robust than the O3I at predicting HUFA balances in the kidney, liver, spleen, and lung. Importantly, increases in both the ω-3 HUFA score (>40%) and the O3I (>10%) were strongly associated with suppression of cSiO 2 -triggered (1) expression of interferon-regulated genes, proinflammatory cytokine production, leukocyte infiltration, and ectopic lymphoid structure development in the lung, (2) pulmonary and systemic autoantibody production, and (3) glomerulonephritis. Collectively, these findings identify achievable ω-3 HUFA scores and O3I thresholds that could be targeted in future human intervention studies querying how ω-3 HUFA consumption influences lupus and other autoimmune diseases.

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

“…As shown here, low and high DHA diets dose-dependently altered relative tissue PUFA content by increasing ω-3 PUFAs and decreasing ω-6 PUFAs, most notably ARA. We recently performed an analysis relating the red blood cell (RBC) ω-3 PUFA levels to disease severity and progression in previous studies we had performed on NZBWF1 mice supplemented with DHA on the background of three unique diets ( 15 ). Most autoimmune and inflammatory endpoints, including inflammatory gene expression, cytokine concentrations, immune cell infiltration, and AAB production negatively correlated with RBC omega-3 levels.…”

“…Lifestyle factors such as diet can also attenuate or potentiate autoimmunity. One potentially promising dietary intervention against lupus is the increased intake of the marine ω-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (C22:6 ω-3; DHA) and eicosapentaenoic acid (C20:5 ω-3; EPA) ( 15 ). Specifically, consumption of ω-3 PUFAs may ameliorate chronic inflammation and autoimmunity by (i) altering membrane function, (ii) modulating gene expression, (iii) competition with inflammatory ω-6 PUFA-generated eicosanoids, and iv) functioning as substrates for metabolism to pro-resolving mediators [reviewed in ( 16 – 18 )].…”

Diet and Hygiene in Modulating Autoimmunity During the Pandemic Era

“…Indeed, supplementation of PUFA such as omega-3 (w−3) augment the activities of antioxidant enzymes and diminish autoimmunity (243). Several studies have shown that w−3 enriched diets dramatically reduce SLE-associated inflammatory markers, lupus progression (mitigating glomerulonephritis) and improve survival in different mouse models of SLE (258)(259)(260)(261)(262). This is achieved mostly through potentiating the effects of antioxidant enzymes (such as superoxide dismutase and glutathione peroxidase) which, in turn, potentiate the ability of renal cells to eliminate harmful free radicals (e.g., reactive oxygen intermediates) (259,261).…”

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

“…A potential promising intervention against cSiO 2 -induced chronic lung inflammation and resultant autoimmunity is increasing dietary intake of the marine polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (C22:6 ω-3; DHA) and eicosapentaenoic acid (C20:5 ω-3; EPA) ( Wierenga et al, 2019 ). Modes of action for ω-3 PUFAs’ ameliorative effects include 1) moderating membrane and lipid raft function, 2) up- and down-regulating gene expression, 3) competing with ω-6 PUFAs and their downstream proinflammatory eicosanoids, and 4) pro-resolving actions of their downstream metabolites [reviewed by Akbar et al (2017) , Calder (2017) , Ferreira et al (2019) , and Wierenga et al (2020) ]. Preclinical ( Halade et al, 2010 ; Halade et al, 2013 ; Pestka et al, 2014 ) and clinical investigations ( Akbar et al, 2017 ; Li et al, 2019b ; Charoenwoodhipong et al, 2020 ; Duarte-Garcia et al, 2020 ) indicate that ω-3 PUFAs can counter onset and progression of lupus symptoms, including nephritis.…”