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Pestka, J. J.

Publications and source records attributed to Pestka, J. J..

2 recordsLinked to original sources
bioRxiv2026

Reducing Glucocorticoid Burden in Lupus with Omega-3 Fatty Acids: Docosahexaenoic Acid Augments Prednisone Efficacy in Maintaining Cyclophosphamide-Induced Remission of Preclinical Lupus Nephritis

BackgroundManaging lupus nephritis (LN) remains challenging due to relapses after immunosuppressive induction and toxicity from long-term glucocorticoid (GC) maintenance therapy. Dietary omega-3 fatty acids prevent LN onset in preclinical models, but their role in maintaining remission post-induction remains unstudied. MethodsThe silica-accelerated LN (SALN) model using lupus-prone NZBWF1 mice was used to evaluate how docosahexaenoic acid (DHA), an omega-3 fatty acid, influenced LN remission durability after cyclophosphamide (CYC) induction, alone or with a moderate dose of prednisone (PDN). Mice received intranasal silica weekly from 8 to 11 weeks. After LN developed at 21 weeks, groups were injected weekly with CYC (human equivalent dose [HED]=31 mg/day) or vehicle (VEH) for 8 weeks, during which CYC groups also received control, DHA (HED=5 g/day), PDN (HED=9 mg/day), or DHA+PDN diets. Disease activity was monitored via proteinuria, autoantibodies, and survival. Six weeks post-CYC, multi-organ histopathology and immunohistochemistry were assessed. ResultsVEH-treated mice developed severe LN with early death. CYC slowed disease temporarily in control- and PDN-fed mice; relapses occurred after cessation. DHA or DHA+PDN increased tissue omega-3 levels and prolonged remission. PDN and DHA monotherapies and co-therapy improved survival, but DHA+PDN was most effective at sustaining remission as reflected by reduced histopathologic markers of lupus severity in the kidney, spleen, lung, and brain. ConclusionDHA+PDN optimally maintained LN remission after CYC, supporting omega-3 supplementation as a potential GC-sparing strategy to improve immunosuppressive therapy and prevent relapses. HighlightsO_LIFrequent post-immunosuppressive treatment flares and the toxicity from long-term maintenance therapy with glucocorticoids (GCs) limit effective management of lupus nephritis (LN). C_LIO_LIThe silica-accelerated lupus nephritis (SALN) model in NZBWF1 mice mimics the gene-environment interactions of human systemic lupus erythematosus (SLE) and LN, enabling synchronized and efficient preclinical studies of drug and nutritional interventions. C_LIO_LIShort-term immunosuppressive therapy with cyclophosphamide (CYC) induces temporary remission of LN and extrarenal inflammation and autoimmunity in SALN mice, which can be extended through monotherapy with either dietary supplementation with omega-3 docosahexaenoic acid (DHA) or a moderate dose of the GC prednisone (PDN). C_LIO_LICombined maintenance therapy with DHA and PDN proved more effective than monotherapy in enhancing the durability of post-CYC LN remission and in reducing extrarenal inflammation and autoimmunity in the lung, spleen, and brain. C_LIO_LIThese preclinical findings show that dietary supplementation with omega-3s such as DHA may offer a safe, affordable, GC-sparing adjunctive option for managing LN and SLE. C_LI

immunology↗
bioRxiv2025

Omega-3 Fatty Acid Synergy with Glucocorticoid in Lupus Macrophages: Targeting Pathogenic Pathways to Reduce Steroid Dependence

IntroductionSystemic 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), suppress inflammation and autoimmunity associated with SLE disease progression. We explored the steroid-sparing potential of DHA to influence suppressive effects of DEX on pathogenic gene expression. MethodsMacrophages from SLE-prone NZBWF1 mice were first subjected to DHA (5, 10, or 25 {micro}M), 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. Effects on gene expression were analyzed by qRT-PCR and RNA-seq. ResultsqRT-PCR indicated that subinhibitory concentrations of DHA (5-10 {micro}M) potentiated the efficacy of low-dose DEX (1-100 nM) in suppressing LPS-induced ISG expression (e.g., Irf7, Oasl1, Rsad2), 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 {micro}M DHA. RNA-seq revealed that combining suboptimal DHA (10 M) 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 that 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-{kappa}B, 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. DiscussionAltogether, DHA and DEX synergistically suppress inflammation 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.

immunology↗