The increasing and often indiscriminate use of medications challenges populations with limited access to effective treatments. Natural compounds such as omega-3 fatty acids (FA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert immunomodulatory effects by incorporating into macrophage membranes and modulating cytokine production and metabolism. This study evaluated the effects of omega-3 FA on inflammatory responses, metabolic reprogramming, and signaling pathways in bone marrow-derived macrophages (BMDMs) infected with Pseudomonas aeruginosa . BMDMs from C57BL/6 mice were pretreated for 3 h with 26 mg DHA and 36 mg EPA, then stimulated with P. aeruginosa (PA14), heat-killed bacteria (HKPA), or lipopolysaccharide (LPS). Omega-3 FA pretreatment reduced pro-inflammatory mediators, including TNF-α, IL-1β, nitric oxide, and NLRP3 expression in macrophages stimulated with PA14, HKPA and LPS, while IL-10 secretion was also reduced under these stimuli. However, omega-3 FA increased IL-10 production under basal conditions. Gene expression analysis revealed upregulation of M2-associated markers ( ARG1 and CD206) , without changes in the M1 marker iNOS . Metabolic and transcriptional analyses demonstrated downregulation of glycolysis-related genes and upregulation of genes associated with mitochondrial function and lipid metabolism. Omega-3 FA did not alter P. aeruginosa proliferation but increased bacteria phagocytosis. Molecular docking suggested that omega-3 FA interact with key inflammatory targets, including GPR120 and PPARγ. Consistently, pharmacological antagonism of PPARγ reversed the omega-3 FA suppressive effects on TNF-α and IL-1β production and NLRP3 expression. These results indicate that omega-3 FA modulates macrophage immune responses and metabolism during P. aeruginosa infection, promoting an anti-inflammatory, metabolically adapted phenotype without impairing bacterial clearance.
Sousa et al. (2026) studied this question.