Macrophage Proresolving Mediators-the When and Where.

Abstract

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.