LAUSR

Bioactive lipid mediators derived from n‐3 and n‐6 fatty acids are known to modulate leukocytes. Metabolic transformation of essential fatty acids to endogenous bioactive molecules plays a major role in human health. Here we tested the potential of substrates; linoleic acid (LA) and docosahexaenoic acid (DHA) and their bioactive products; resolvin D1 (RvD1) and 12‐ S‐hydroxyeicosatetraenoic acids (HETE) to modulate macrophage plasticity and cardiac fibroblast phenotype in presence or absence of lipid metabolizing enzyme 12/15‐lipoxygenase (LOX). Peritoneal macrophages and cardiac fibroblasts were isolated from wild‐type (C57BL/6J) and 12/15LOX −/− mice and treated with DHA, LA, 12(S)‐HETE, and RvD1 for 4, 8, 12, and 24 hr. LA, DHA, 12(S)‐HETE, and RvD1 elicited mRNA expression of proinflammatory markers; tumor necrosis factor‐α ( Tnf‐α), interleukin 6 ( IL‐6), chemokine (C–C motif) ligand 2 (Ccl2), and IL‐1β in wild type (WT) and in 12/15LOX −/− macrophages at early time point (4 hr). Bioactive immunoresolvent RvD1 lowered the levels of Tnf‐α, IL‐6, and IL‐1β at 24 hr time point. Both DHA and RvD1 stimulated the proresolving markers such as arginase 1 ( Arg‐1), chitinase‐like protein 3 ( Ym‐1), and mannose receptor C‐type 1 in WT macrophage. RvD1 induced proresolving phenotype Arg‐1 expression in both WT 12/15LOX −/− macrophages even in presence of 12(S)‐HETE. RvD1 peaked 5LOX expression in both WT and 12/15LOX −/− at 24 hr time point compared with DHA. RvD1 diminished cyclooxygenase‐2 but upregulated 5LOX expression in fibroblast compared with DHA. In summary, the feed‐forward enzymatic interaction with fatty acids substrates and direct mediators (RvD1 and 12(S)‐HETE) are responsive in determining macrophages phenotype and cardiac fibroblast plasticity. Particularly, macrophages and fibroblast phenotypes are responsive to milieu and RvD1 governs the milieu‐dependent chemokine signaling in presence or absence of 12/15LOX enzyme to resolve inflammation.