Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
Microbiol Spectr. 2016 Jun;4(3). doi: 10.1128/microbiolspec.MCHD-0001-2014.
Macrophages and neutrophils orchestrate acute inflammation and host defense as well as the resolution phase and return to homeostasis. In this article, we review the contribution of macrophages to local lipid mediator (LM) levels and the regulation of macrophage LM profiles by polymorphonuclear neutrophils and neutrophil-derived microparticles. We carried out LM metabololipidomics, profiling distinct phagocytes: neutrophils (PMNs), apoptotic PMNs, and macrophages. Efferocytosis increased specialized proresolving mediator (SPM) biosynthesis, including resolvin D1 (RvD1), RvD2, and RvE2, which were further elevated by PMN microparticles. In studies using deuterium-labeled precursors (d8-arachidonic acid, d5-eicosapentaenoic acid, and d5-docosahexaenoic acid), apoptotic PMNs and microparticles contributed to SPM biosynthesis during efferocytosis. Assessment of macrophage LM profiles in M2 macrophages demonstrated higher SPM levels in this macrophage subset, including maresin 1 (MaR1), and lower amounts of leukotriene B4 (LTB4) and prostaglandins than in M1. Apoptotic PMN uptake by both macrophage subtypes led to modulation of their LM profiles. LTB4 was downregulated in M2, whereas SPMs including lipoxin A4 were increased. Conversely, uptake of apoptotic PMNs by M2 macrophages reduced (∼25%) overall LMs. MaR1 displays potent tissue-regenerative and antinociceptive actions in addition to its proresolving and anti-inflammatory actions. In addition, the MaR1 biosynthetic intermediate 13S,14S-epoxy-maresin is also bioactive, inhibiting LTB4 biosynthesis and switching macrophage phenotypes from M1 to M2. Together, these results establish LM signature profiles of human phagocytes and related subpopulations. They demonstrate microparticle regulation of macrophage-specific endogenous LMs during defined stages of acute inflammation and their dynamic changes in human primary phagocytes.
巨噬细胞和中性粒细胞协调急性炎症和宿主防御以及解决阶段和恢复到体内平衡。在本文中，我们回顾了巨噬细胞对局部脂质介质 (LM) 水平的贡献，以及多形核中性粒细胞和中性粒细胞衍生的微粒对巨噬细胞 LM 谱的调节。我们进行了 LM 代谢脂质组学分析，分析了不同的吞噬细胞：中性粒细胞 (PMN)、凋亡的 PMN 和巨噬细胞。吞噬作用增加了特殊的促解决介质 (SPM) 的生物合成，包括 resolvin D1 (RvD1)、RvD2 和 RvE2，PMN 微粒进一步增加了它们的水平。在使用氘标记前体 (d8-花生四烯酸、d5-二十碳五烯酸和 d5-二十二碳六烯酸) 的研究中，凋亡的 PMN 和微粒在吞噬作用期间有助于 SPM 的生物合成。在 M2 巨噬细胞中评估巨噬细胞 LM 谱时，发现该巨噬细胞亚群中的 SPM 水平较高，包括maresin 1 (MaR1)，而 LTB4 和前列腺素的含量低于 M1。两种巨噬细胞亚型摄取凋亡的 PMN 都会导致其 LM 谱的调节。M2 中 LTB4 下调，而 SPM 包括脂氧素 A4 增加。相反，M2 巨噬细胞摄取凋亡的 PMN 会减少 (约 25%) 整体 LMs。MaR1 除了具有促解决和抗炎作用外，还具有很强的组织再生和抗伤害作用。此外，MaR1 生物合成中间体 13S,14S-环氧maresin 也是生物活性的，抑制 LTB4 生物合成并将巨噬细胞表型从 M1 转换为 M2。总之，这些结果确立了人类吞噬细胞及其相关亚群的 LM 特征谱。它们表明微粒在急性炎症的特定阶段调节巨噬细胞特异性内源性 LMs，以及它们在人类原代吞噬细胞中的动态变化。
