The Role of Maresins in Inflammatory Pain: Function of Macrophages in Wound Regeneration

Abstract

Although acute inflammatory responses are host-protective and generally self-limited, unresolved and delayed resolution of acute inflammation can lead to further tissue damage and chronic inflammation. The mechanism of pain induction under inflammatory conditions has been studied extensively; however, the mechanism of pain resolution is not fully understood. The resolution of inflammation is a biosynthetically active process, involving specialized pro-resolving mediators (SPMs). In particular, maresins (MaRs) are synthesized from docosahexaenoic acid (DHA) by macrophages and have anti-inflammatory and pro-resolving capacities as well as tissue regenerating and pain-relieving properties. A new class of macrophage-derived molecules-MaR conjugates in tissue regeneration (MCTRs)-has been reported to regulate phagocytosis and the repair and regeneration of damaged tissue. Macrophages not only participate in the biosynthesis of SPMs, but also play an important role in phagocytosis. They exhibit different phenotypes categorized as proinflammatory M1-like phenotypes and anti-inflammatory M2 phenotypes that mediate both harmful and protective functions, respectively. However, the signaling mechanisms underlying macrophage functions and phenotypic changes have not yet been fully established. Recent studies report that MaRs help resolve inflammatory pain by enhancing macrophage phagocytosis and shifting cytokine release to the anti-inflammatory M2 phenotypes. Consequently, this review elucidated the characteristics of MaRs and macrophages, focusing on the potent action of MaRs to enhance the M2 macrophage phenotype profiles that possess the ability to alleviate inflammatory pain.

Keywords: inflammation; macrophage; maresin; pain; specialized pro-resolving mediators.

Figure 1

Biosynthesis of specialized pro-resolving mediators (SPMs) derived from omega-3 and omega-6 polyunsaturated fatty acids (PUFAs).

Figure 2

The outcome of acute inflammation and resolution. Under stimulation of injury or infection, release of proinflammatory lipids (prostaglandin (PG), leukotriene (LT)), chemokines (C-C motif chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8)), and cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-6) induce the recruitment of neutrophils. Other immune cells (macrophages, B cells, and T cells) also participate in the process. Macrophages directly phagocytize organisms and apoptotic neutrophils, while B cells are converted into plasma cells to kill organisms through secreted antibodies, referred to as antibody-dependent cell-mediated cytotoxicity. Macrophages and B cells activate T cells via antigen cross presentation (AP). PGE2 leads to vasodilation and LTB4 stimulates PMN influx into the inflammatory locus. Subsequently, lipid mediator (LM) class switching converts proinflammatory signals into pro-resolving signals and triggers resolution. SPMs restrict excessive PMN influx to the injury site, enhance efferocytosis, and stimulate pro-resolving signals.

Figure 3

Synthesis and function of maresins (MaRs) and macrophages. (A) MaRs and MaR conjugates in tissue regeneration (MCTRs) biosynthesis. Human macrophage 12-LOX converts DHA to the 13S,14S-epoxy-maresin intermediate and hydrolase or soluble epoxide hydrolase is converted to MaR1 and MaR2, respectively. The MCTR biosynthetic pathway is initiated by lipoxygenation of 14S-HpDHA, converted by lipoxygenase activity to the 13S,14S-epoxy-maresin intermediate. MCTR1 is catalyzed by glutathione s-transferase mu4 (GSTM4) and/or leukotriene C4 synthase (LTC4S). MCTR1 is converted by gamma-glutamyl transferase (GGT) to MCTR2, which then acts as a substrate for conversion by dipeptidase (DPEP) to MCTR3. (B) M1 and M2 polarization of macrophages. Bone marrow-derived macrophages differentiate into mononuclear cells and gradually become mature macrophages that can be released into circulation. IFN-γ, TNF-α, and LPS stimulate macrophages into M1, IL-4 and IL-13 into M2a, IC and TLR into M2b, and IL-10 into M2c; A2AR agonist stimulates them into M2d. M1 macrophages induce a proinflammatory response, whereas M2 macrophages induce an anti-inflammatory response. M1 macrophages can also differentiate into M2 macrophages through local cues. The M1 phenotype is proinflammatory, phagocytic, and bactericidal, while the M2 macrophages act to switch off inflammation. IFN-γ: interferon gamma; TNF-α: tumor necrosis factor alpha; LPS: lipopolysaccharides; IC: immune complexes; TLR: toll-like receptor; A2AR: adenosine A2A receptor; IL: interleukin; IL-1R: IL-1 receptor.

Figure 4

Maresins regulate macrophage phenotype and resolution of inflammatory pain. Maresins (MaRs) improve M2 macrophage function, shifting cytokine release to an anti-inflammatory profile and thereby facilitating the resolution of inflammatory pain.