**1. Introduction**

Inflammation is an immune response to harmful stimuli, including pathogens, damaged cells, toxic compounds, surgery, or irradiation [1]. Inflammation is characterized by swelling, heat, pain, redness, and loss of tissue function, which is caused by local immune, vascular, and inflammatory cell responses to infection or injury [2]. Inflammatory processes that include changes in vascular permeability, recruitment and accumulation of leukocytes, and release of inflammatory mediators, are important in the regeneration of injured tissues [3]. Therefore, inflammation is an essential defense mechanism for preserving health. A weak inflammatory response can lead to tissue destruction by harmful stimuli, while chronic unresolved inflammation may culminate in various pathological conditions, including cancer, fibrosis, and pain [4]. Wound regeneration promotes resolution of inflammation by restoring barrier function [5]. Neutrophils are the first circulating inflammatory cells to be recruited to the wound site [6]. Clinical observations demonstrating that leukocyte recruitment

disorders and reduced neutrophil infiltration are associated with delayed wound healing indicate the importance of neutrophils for e fficient wound repair [7]. Recent studies have shown that macrophages exhibit di fferent functions during the immune response, with proinflammatory signaling occurring during the early stages of inflammation and, once inflammation is resolved, promotion of tissue regeneration at late stages [8,9].

Inflammatory pain indicates increased mechanical and thermal sensitivity due to inflammatory reactions [10]. These mechanisms have been extensively investigated over the past two decades [11,12]. The earliest factors causing inflammatory pain are lipid mediators (leukotrienes (LTs) and prostaglandins (PGs)) and proinflammatory cytokines (Tumor necrosis factor (TNF)- α and interleukin (IL)-1β) [13]. They sensitize nociceptors of the primary sensory neurons (peripheral sensitization) through modulation of ion channels including TRP channels [14–16]. However, our understanding of the resolution processes and mechanisms that causes inflammatory pain is limited. The acute inflammatory response is protective, evolved to repair damaged tissues and eliminate invading organisms [17,18]. This is ideally a self-limited inflammatory response that leads to a complete resolution of leukocyte infiltrates and removal of cellular debris, allowing for the return to normal homeostasis [18]. However, uncontrolled or unresolved acute inflammatory conditions can lead to chronic inflammation, causing greater tissue damage, tissue remodeling disorders, and poor tissue healing [19,20]. These conditions are known to induce the transition to chronic and maladaptive inflammatory pain [21,22] and may lead to vascular disease, metabolic syndromes, and neurological diseases [19].

In general, the resolution of acute inflammation is an active rather than a passive process that requires the biosynthesis of SPMs including lipoxins (LXs), resolvins (Rvs), protectins (PDs), and maresins (MaRs), derived from the omega-6 fatty acid arachidonic acid (AA) and the omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) [23]. SPMs turn o ff the inflammatory response by acting on distinct G-protein-coupled receptors expressed in immune cells that activate dual anti-inflammatory and pro-resolution activity in various animal models of inflammation [24–26]. In response to injury or infection, an acute inflammatory response involves early tissue edema and neutrophil infiltration, some of which transits to mature macrophages [27,28]. Macrophages are major repair mediators in peripheral nerve and spinal cord injuries [29] that exist in two polarization states [30]. These states are not fixed but instead change rapidly in response to the microenvironment [31–33]. M1 (classically activated) macrophages produce proinflammatory cytokines and promote nociceptor sensitization that can be converted into inflammatory pain, whereas M2 (alternatively activated) macrophages produce anti-inflammatory cytokines and promote wound healing [34]. Based on these functional roles, macrophages regulate the enhancement or alleviation of pain sensitivity under various conditions [32,35]. For example, M1 infiltration has been identified in pain-associated synovial tissue in models of muscle, joint, and paw inflammation [35,36]. In contrast, M1 deficiency has been reported to reduce increased proinflammatory cytokines and prevent local inflammatory pain in response to proinflammatory agents or chemotherapy-induced peripheral neuropathy [37]. The transition from M1 to M2 phenotypes—or the balance thereof—appears to be crucial for resolution associated with acute inflammatory response [13,38]. Spinal cord injury (SCI), a condition frequently associated with prolonged inflammatory pain, increases the abundance of M1 phenotype cells in the spinal cord [13]. Thus, the balance of M1/M2 macrophages plays an important role in the resolution of inflammation and inflammatory pain relief.

MaRs are believed to act as potent protective mediators of macrophage function [39,40] and promote the resolution of acute inflammation and tissue regeneration [23,41,42]. Recent studies report that MaRs promote inflammatory activity in macrophages; furthermore, the incubation of human macrophages with MaRs improves resolution by increasing phagocytosis and e fferocytosis. These effects are likely due to various substances released by MaRs that alter macrophage function and possibly contribute to the resolution of inflammation. For example, biosynthesized MaRs downregulate proinflammatory cytokines, such as IL-1β, IL-6, and TNFα, to induce inflammation resolution and tissue regeneration [43,44]. However, defective or delayed resolution causes chronic inflammation that can eventually lead to chronic inflammatory pain [20]. It has been reported that inflammatory resolution is reduced due to the following functional problems of the lipid mediator family and macrophages: (a) M1/M2 macrophage imbalance [45,46]; (b) reduced MaR or other SPM formation [27,42,47–49]; (c) impaired synthesis of DHA [50]; and (d) aging [2,51,52]. Therefore, MaRs may act directly or indirectly to reverse the inflammation relief deficiencies caused by these functional problems, thereby restoring normal inflammation relief function. Moreover, a new series of bioactive peptide-lipid conjugated mediators—MCTRs—are produced in the later stages of self-resolved infection [23,41] that regulate inflammation and resolution mechanisms as well as tissue regeneration [23,41]. Consequently, this review described the functional mechanisms of MaRs based on their potential ability to control macrophage activation and inflammatory resolution.
