Immune responsive resolvin D1 programs peritoneal macrophages and cardiac fibroblast phenotypes in diversified metabolic microenvironment.

ABSTRACT: 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-? ( Tnf-?), interleukin 6 ( IL-6), chemokine (C-C motif) ligand 2  (Ccl2), and IL-1? in wild type (WT) and in 12/15LOX -/- macrophages at early time point (4?hr). Bioactive immunoresolvent RvD1 lowered the levels of Tnf-?, IL-6, and IL-1? 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.

SUBMITTER: Kain V 

PROVIDER: S-EPMC6317995 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature