Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama.
J Cell Physiol. 2019 Apr;234(4):3910-3920. doi: 10.1002/jcp.27165. Epub 2018 Sep 7.
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.
源自 n-3 和 n-6 脂肪酸的生物活性脂质介质已知可调节白细胞。必需脂肪酸向内源性生物活性分子的代谢转化在人类健康中起着重要作用。在这里，我们测试了底物亚油酸（LA）和二十二碳六烯酸（DHA）及其生物活性产物 12- S-羟基二十碳四烯酸（12(S)-HETE）和分辨率 D1（RvD1）的潜力，以调节存在或不存在脂质代谢酶 12/15-脂氧合酶（LOX）的巨噬细胞可塑性和心肌成纤维细胞表型。从野生型（C57BL/6J）和 12/15LOX 小鼠中分离出腹腔巨噬细胞和心肌成纤维细胞，并分别用 DHA、LA、12(S)-HETE 和 RvD1 处理 4、8、12 和 24 小时。LA、DHA、12(S)-HETE 和 RvD1 在野生型（WT）和 12/15LOX 巨噬细胞中早期（4 小时）诱导促炎标志物的 mRNA 表达；肿瘤坏死因子-α（Tnf-α）、白细胞介素 6（IL-6）、趋化因子（C-C 基序）配体 2（Ccl2）和白细胞介素 1β。生物活性免疫调节剂 RvD1 在 24 小时时间点降低了 Tnf-α、IL-6 和 IL-1β 的水平。DHA 和 RvD1 均刺激 WT 巨噬细胞中促修复标志物，如精氨酸酶 1（Arg-1）、几丁质样蛋白 3（Ym-1）和甘露糖受体 C 型 1。RvD1 甚至在 12(S)-HETE 存在的情况下诱导 WT 和 12/15LOX 巨噬细胞中的促修复表型 Arg-1 表达。与 DHA 相比，RvD1 在 24 小时时间点使 WT 和 12/15LOX 中的 5LOX 表达达到峰值。RvD1 降低了成纤维细胞中环氧化酶-2 的表达，但上调了 5LOX 的表达，与 DHA 相比。总之，脂肪酸底物和直接介质（RvD1 和 12(S)-HETE）的前馈酶相互作用在决定巨噬细胞表型和心肌成纤维细胞可塑性方面具有反应性。特别是，巨噬细胞和成纤维细胞表型对环境有反应，并且 RvD1 在存在或不存在 12/15LOX 酶的情况下控制环境依赖性趋化因子信号，以解决炎症。
