**1. Introduction**

Endometriosis is a chronic, inflammatory and estrogen-dependent disease characterized by endometrial tissue outside the uterine cavity. It affects approximately 10% of women of reproductive age and is associated with chronic pelvic pain and infertility [1]. The pathophysiology of endometriosis is controversial. Sampson's (1927) retrograde menstruation theory is still the most accepted, describing that the reflux of endometrial fragments would allow the implantation of these cells outside the uterus, especially in the pelvic cavity [2]. However, genetic, neuronal, hormonal and immunological variations may facilitate the adhesion and development of endometrial implants [3].

It is known that 17-β-estradiol (E2) plays a strong influence on the development and progression of endometriosis, acting via estrogen receptors (ER) that are abundant in reproductive tissues, in addition to activating several intracellular signaling cascades in the inflammatory process [4].

Several studies demonstrate that the immune response plays an essential role in the genesis of endometriosis. Many active immune cells, especially peritoneal macrophages,

**Citation:** de Fáveri, C.; Fermino, P.M.P.; Piovezan, A.P.; Volpato, L.K. The Inflammatory Role of Pro-Resolving Mediators in Endometriosis: An Integrative Review. *Int. J. Mol. Sci.* **2021**, *22*, 4370. https://doi.org/10.3390/ ijms22094370

Academic Editor: Antonio Simone Laganà

Received: 31 March 2021 Accepted: 19 April 2021 Published: 22 April 2021

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are involved in the development, maintenance and progression of endometrial lesions [1]. High concentrations of cytokines, growth factors and angiogenic factors are observed in the peritoneal fluid of subjects with endometriosis [5]. Interleukins, tumor necrosis factors (TNF) and other chemotactic cytokines act as recruiting macrophages and T lymphocytes to the peritoneum, modulating the inflammatory response associated with endometriosis [6]. Among the factors that support the invasive and proliferative activity of endometrial implants, the epithelial-mesenchymal transition (EMT) is characterized as a biological process in which cells lose cell polarity cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells [7]. Additionally, matrix metalloproteinases (MMPs) act out as cell-matrix remodeling enzymes that induce the release of growth factors and pro-inflammatory cytokines, favoring the progression of inflammation angiogenesis, tissue remodeling and, therefore, contributing to the implantation and increase of endometriotic lesions [8].

Furthermore, cellular signaling proteins such as p38 MAPK (p38 mitogen-activated protein kinases) and ERK (extracellular signal-regulated kinase) are critical in the inflammatory response. They are characterized as intracellular signal transduction molecules activated by phosphorylation via membrane receptors, increasing levels of cytokines such as interleukins, and TNF, in addition to increasing MMP activity. In addition, several studies show its influence on the pathogenesis of endometriosis [9]. The multidrug resistance-associated protein 4 (MRP4) can transport several endogenous molecules, playing a critical role in cellular communication and signaling. Among these molecules, there is a strong affinity with Prostaglandin E2 (PGE2), consequently potentiating the inflammatory process [10].

Several inflammatory response events can limit their magnitude and duration [5]. The resolution of inflammation is an active process where the activation of endogenous factors allows the host tissue to maintain homeostasis [11]. This process occurs differently concerning the known anti-inflammatory pathways since the pro-resolving molecules act in a multifactorial way at the inflammatory site. In addition to producing powerful signals to reduce neutrophils and eosinophils' infiltration, they also promote the uptake and elimination of apoptotic cells and microorganisms by macrophages at the inflamed tissue. At the beginning of the inflammatory process, classic lipid mediators such as prostaglandins and leukotrienes are released, activating and amplifying the inflammatory process. After the acute phase, some of these molecules start to produce substances that synthesize endogenous mediators with anti-inflammatory and pro-resolving activity, such as lipoxins, resolvins, protectins and maresines [12–14].

The pro-resolving mediators (PRM) are lipids or proteins. Lipid mediators are generated through lipoxygenases (LOX) and cyclooxygenases (COX) by the metabolism of arachidonic acid (AA), such as lipoxins, or originated from omega-3 polyunsaturated fatty acids (omega-3 PUFAS), represented by the acid eicosapentaenoic (EPA)-derived resolvin E (RvE) and docosahexaenoic acid (DHEA)-derived resolvin D (RvD), protectins and maresines. These mediators promote the sequestration of pro-inflammatory cytokines, in addition to removing polymorphonuclear cells (PMN) from the epithelial surface, phagocyting apoptotic PMNs, removing inflammatory residues through the lymphatic vessels and reducing inflammatory pain [15–17].

In endometriosis, the signaling pathways for Lipoxin A4 (LXA4) are the most studied. Its cascades are mediated by several membrane receptors [18] with higher affinity for the formyl peptide 2/"aspirin-triggered lipoxin" receptor (FPR2/ALX); therefore, most studies show how LXA4 acts through this receptor [19], allowing it to act in a double, anti-inflammatory and pro-resolutive manner [12]. Some works have already shown that LXA4 presents a high structural similarity with estriol, a weak agonist of the ER-α in the endometrium's epithelial cells. For this reason, LXA4 can also occupy these receptors and decrease E2-mediated signaling, triggering anti-inflammatory and pro-resolving effects, in addition to modulating the expression of ERs [4,18,20].

The PRM proteins are Annexin A1 (ANXA1), galectins and melanocortins. These mediators have a crucial modulating function in neutrophil trafficking. They can reduce infiltration, activate apoptosis at the inflammatory site, stimulate phagocytosis and the elimination of apoptotic neutrophils, in addition to inducing the phenotypic change from inflammatory M1 macrophages to M2 anti-inflammatory macrophages, which causes a reparative response [17,21,22]. ANXA1 is a calcium-dependent phospholipid-binding protein and has been observed as an anti-inflammatory mediator, regulating physiological and pathological cellular processes. Additionally, ANXA1 is expressed in several tissues, including the endometrium, where it acts via the FPR2/ALX and other mediators [23].

The FPR2/ALX regulates the action of PRM, such as ANXA1 and LXA4, belonging to the superfamily of formyl peptide receptors. These receptors are critical in endometriosis since the expression of FPR2/ALX proved to be more significant in the cells of endometriotic lesions compared to the normal endometrium. In addition, these receptors are regulated by estrogen and other cytokines and mediate specific cellular pathways to suppress inflammation [18,23].

Failures in these pro-resolving pathways can predispose the host to chronic inflammatory diseases [12]. In this process, cellular mechanisms and their biochemical pathways open new strategies for potential therapeutic interventions [24]. Evidence that PRM are promising targets for the development of pharmacological treatments for chronic inflammatory diseases is pointed out by Serhan (2017); in this, the author demonstrates examples of conditions for which drugs like PRM have been successfully studied in clinical trials in humans (phase I and phase II), including periodontal diseases, inflammation associated with dry eye and childhood eczema [25].

The mediators that act as PRM in endometriosis are still little explored. Thus, this review aims to synthesize the information available in the literature regarding the inflammatory role of PRM in endometriosis.
