Omega-3 fatty acid synergy with glucocorticoid in mouse lupus macrophage model: targeting pathogenic pathways to reduce steroid dependence.

Introduction: Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by aberrant inflammation, type I IFN-stimulated gene (ISG) expression, and autoantibody production. Glucocorticoids (GCs) like dexamethasone (DEX) are standard long-term SLE treatments but cause significant side effects, highlighting the need for safer steroid-sparing options. Preclinical and clinical studies suggest that dietary supplementation with omega-3 fatty acids (O3FAs), particularly docosahexaenoic acid (DHA), suppresses inflammation and autoimmunity associated with SLE disease progression. We explored the steroid-sparing potential of DHA to influence the suppressive effects of DEX on pathogenic gene expression. Methods: Macrophages from SLE-prone NZBWF1 mice were first subjected to DHA (5, 10, or 25 µM), DEX (1, 10, 100, or 1000 nM), or DHA+DEX cotreatment. Following pretreatment, cells were exposed to lipopolysaccharide (LPS; 20 ng/mL) to model SLE hyperinflammation. Resultant gene expression was subjected to synergy and deconvolution analysis. Results: qRT-PCR indicated that subinhibitory concentrations of DHA (5-10 µM) potentiated the efficacy of low-dose DEX (1-100 nM) in suppressing LPS-induced ISG expression (e.g., Discussion: Altogether, DHA and DEX synergistically suppress inflammatory gene expression by targeting common and unique molecular pathways in SLE macrophages, favoring the pro-resolving M2 phenotype. O3FA-GC cotreatment might facilitate reducing requisite steroid dosages for SLE management.