{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T21:42:23Z","timestamp":1792618943207,"version":"4.5.0"},"reference-count":129,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Macrophages from SLE-prone NZBWF1 mice were first subjected to DHA (5, 10, or 25 \u00b5M), 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>qRT-PCR indicated that subinhibitory concentrations of DHA (5-10 \u00b5M) potentiated the efficacy of low-dose DEX (1\u2013100 nM) in suppressing LPS-induced ISG expression (e.g., <jats:italic>Irf7<\/jats:italic>, <jats:italic>Oasl1<\/jats:italic>, <jats:italic>Rsad2<\/jats:italic>), amplifying the effects of DEX monotherapy by 10- to 100-fold. SynergyFinder analysis confirmed that DHA and DEX interacted synergistically in suppressing ISG expression, with significant inhibition observed at concentrations as low as 1 nM DEX and 5 \u00b5M DHA. RNA-seq revealed that combining suboptimal DHA (10 \u03bcM) and DEX (100 nM) induced 247 differentially expressed genes (DEGs) at 4 hr and 347 DEGs at 8 hr post-LPS, dramatically surpassing the effects of each treatment alone. Functional enrichment analysis indicated DHA+DEX cotreatment robustly suppressed immune and inflammatory pathways while promoting proliferative and metabolic processes, reflecting a shift from inflammatory (M1) to pro-resolving (M2) macrophage phenotypes. DHA and DEX countered LPS effects by i) downregulating common transcription factors (TFs) canonically associated with inflammation (e.g., NF-\u03baB, AP-1, STATs, and IRF1), ii) upregulating shared regulatory factors involved in inflammation resolution (e.g., YBX1, EGR1, and BCL6), and iii) selectively influencing other regulatory factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1646133","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T05:42:23Z","timestamp":1760506943000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Omega-3 fatty acid synergy with glucocorticoid in mouse lupus macrophage model: targeting pathogenic pathways to reduce steroid dependence"],"prefix":"10.3389","volume":"16","author":[{"given":"Lauren K.","family":"Heine","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rance","family":"Nault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalen","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley 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