{"paper_id":"c60f5b9a-5147-461e-8c6e-1bf1375bfd73","body_text":"The role of Lipoxin A 4 in endometrial biology and\nendometriosis\nGO Canny 1 and BA Lessey 2\nLipoxin A4 (LXA4), an endogenous anti-inflammatory and immunomodulatory mediator studied in many disease states, is\nrecently appreciated as a potentially significant player in the endometrium. This eicosanoid, synthesized from\narachidonic acid via the action of lipoxygenase enzymes, is likely regulated in endometrial tissue during the menstrual\ncycle. Recent studies revealed that LXA4 acts as an estrogen receptor agonist in endometrial epithelial cells, antagonizing\nsome estrogen-mediated activities in a manner similar to the weak estrogen estriol, with which it shares structural\nsimilarity. LXA\n4 may also be an anti-inflammatory molecule in the endometrium, though its precise function in various\nphysiological and pathological scenarios remains to be determined. The expression patterns for LXA4 and its receptor in\nthe female reproductive tract suggest a role in pregnancy . The present review provides an oversight of its known and\nputative roles in the context of immuno-endocrine crosstalk. Endometriosis, a common inflammatory condition and a\nmajor cause of infertility and pain, is currently treated by surgery or anti-hormone therapies that are contraceptive and\nassociated with undesirable side effects. LXA4 may represent a potential therapeutic and further research to elucidate its\nfunction in endometrial tissue and the peritoneal cavity will undoubtedly provide valuable insights.\nINTRODUCTION\nThe female reproductive tract maintains an immune surveil-\nlance system similar to other mucosal surfaces, serving as the\nfront line against pathogens. The uterus is unique given its roles\nin the transport of male gametes and processing of seminal\nantigens. Immune crosstalk appears vital to the success of\npregnancy and for tolerance of the fetal semi-allograft\nduring implantation and throughout gestation.\n1 In addition,\nin menstruating species such as humans and most primates, the\ncyclic shedding of the upper two-thirds of the endometrial\nsurface requires rapid healing and regeneration while\nmaintaining those defenses and minimizing inflammatory\nresponses.\n2\nOvulation, menstruation, implantation, and parturition all\nrepresent short-term inflammatory events 3 limited by endo-\ngenous mediators that facilitate resolution of inflammation.\nHealth is maintained by the balance between inflammation and\nmetabolic and immune homeostasis, especially important at\nmucosal surfaces such as the female reproductive tract. A\ndisequilibrium in the inflammatory response to disease\nunderlies many immune-mediated illnesses.\n4–8 Lipoxins\n(LXs), as well as the more recently discovered Resolvins\nand Protectins, are specialized pro-resolving mediators essen-\ntial for the resolution of inflammation9 In this review, we focus\non a molecule likely central to this balancing act in endometrial\ntissue, Lipoxin A 4 (LXA4).\nLXA4 has been implicated as an anti-inflammatory mediator\nin human cycling endometrium and following parturition. 10,11\nThe significance of LXA 4 in normal endometrial physiology is\ndifficult to gauge given the complexities of its signaling via\ndifferent receptors with varying roles in multiple cell types as\nwell as the paucity of published data concerning its function\n(Figure 1). As an immune modulator, LXA\n4 has been shown in\nother systems to inhibit leukocyte migration, 12 leukotriene-\ninduced responses, including vasoconstriction and chemotactic\nresponses,\n13,14 and mitogenic signals.15 Based on recent studies,\nLXA4 and related mediators are likely to contribute to\nendometrial biology serving as a fulcrum between opposing\nforces to help maintain the balance required for tissue repair/\nwound healing during menstruation, tolerance toward the\nnascent embryonic fetal allograft, maintenance of pregnancy,\nand the initiation and resolution of parturition. Additionally, as\nattenuated LXA\n4 production may contribute directly to many\ninflammatory conditions and chronic disease states, 16–20\n1Geneva Foundation for Medical Education and Research, Versoix, Switzerland and 2University of South Carolina School of Medicine—Greenville, Greenville, SC, USA.\nCorrespondence: GO Canny (Geraldine.Canny@gmail.com)\nReceived 4 July 2012; accepted 16 January 2013; published online 13 March 2013. doi:10.1038/mi.2013.9\nnature publishing group REVIEW\nMucosalImmunology | VOLUME 6 NUMBER 3 | MAY 2013 439\n\ndysregulation of LXA 4 actions may significantly impact\nendometrial health and reproductive function.\nLIPOXIN A 4 BIOSYNTHESIS AND LIPOXYGENASE\nMETABOLITES\nIn humans, the major LX biosynthetic pathways involve\nbiosynthesis during specific cell:cell interactions and upon\npriming by cytokines\n21,22 in the vasculature and at mucosal\nboundaries, such as the endometrium. LX production occurs in\na transcellular manner at sites of inflammation involving two\ndifferent cell types such as epithelial cells and neutrophils, for\nexample. Three human lipoxygenase (LOX) enzymes, iron-\ncontaining enzymes that catalyze the hydroperoxidation of\npolyunsaturated fatty acids, have been cloned: 5-LOX, 12-LOX,\nand 15-LOX.\n23,24 The sequential oxygenation of arachidonic\nacid results in LX formation. Aspirin triggers the generation of\nepimeric forms of LXs known as aspirin-triggered LXs, such as\n15-epi-LXA\n4,25 an attribute also shared by statins. 26,27 15-\nALOX type 2, which exhibits a substrate preference for\narachidonic acid converting it to 15S-hydroperoxyeicosate-\ntraenoic acid (15S-HETE),\n24 is expressed in human endome-\ntrium.28 However, human 15-LOX isoforms exhibit allosteric\nproduct regulation, 29 and the functional significance of feed-\nback loops in vivo merits further investigation.\nInterleukin 13 (IL-13), is a potent inducer of 15-LOX gene\nexpression and enzyme activity in human monocytes, 30\nrequiring ERK1/2 MAPK (extracellular signal–regulated kinase\n1/2/ mitogen-activated protein kinase) activation.\n31 IL-13 was\nalso shown to induce the mouse homolog 12/15-LOX in\nmonocytes while IFN- g (interferon gamma) inhibited expres-\nsion and activity of this enzyme. IL-4 also induced 12/15-LOX\nin mouse myeloid cells.\n32 Both IL-4 and IL-13 are involved in\ndifferentiation of monocytes into M2 macrophages, which\nexhibit an immunosuppressive phenotype when compared\nwith M1 macrophages.\n33\n12/15-LOX is a progesterone target gene in the mouse uterus,\nbased on the progesterone receptor knockout mouse model. 34\nThere is precedent for hormonal regulation of this enzyme in\nmucosal tissues, such as the cornea, where 17 b-estradiol (E2)\ndownregulates 15-LOX as well as LXA\n4 formation.35 In prostate\ncancer cells, glucocorticoids inhibit this enzyme, 36 and in\nvascular smooth muscle cells aldosterone stimulates 12/15-\nLOX expression.\n37 In prostate epithelial cells, peroxisome\nproliferator–activated receptor-gamma (PPAR- g) interacts\nwith the orphan receptor ROR-a to bind the 15-LOX promoter,\nproviding a novel negative feedback mechanism for 15-LOX\nand therefore LXA4 production.38 It remains to be seen whether\nsuch regulatory mechanisms are germane to the human\nendometrium.\nLXA\n4 levels are high at the end of the menstrual cycle and\nthen decline after menses.10 That is, coincidently, the time when\nIL-13 peaks during the normal menstrual cycle.39 As previously\nnoted, estrogen-mediated inhibition of this enzyme 35 would fit\nwell with the observation that LXA 4 levels decline during the\nproliferative phase coincident with a rise in E2. 10 The increase\nin LXA 4 levels during pregnancy is likely due to human\nchorionic gonadotropin, which promotes LXA 4 release in the\ndecidua of human endometrium. 10\nLOX metabolites have been implicated in reproductive\nfunction for over three decades. One study in mice provided\ndirect evidence of the importance of LOX metabolites during\nimplantation.34 Using conditional PR knockout mice it was\nestablished that leukocyte and epidermal 12/15-LOX were\ndownstream targets of PR in uterine surface epithelium. At\nimplantation, maximal induction of both 12/15-LOX enzymes\nwas observed, with a parallel increase in the eicosanoid\nmetabolites 12-HETE, 15-HETE, and 13-HODE (13-(S)-\nhydroxyoctadecadienoic acid) in the uterus. Furthermore,\nleukocyte 12/15-LOX null mice exhibited impaired implanta-\ntion and usage of a 12/15-LOX inhibitor confirmed these\nresults, leading to a significant reduction in implantation sites.\n12-HETE, 15-HETE, and 13-HODE activated PPAR- g in cell-\nbased assays, and Rosiglitazone, a PPAR-g agonist, reversed the\nability of a LOX inhibitor to inhibit implantation. This was the\nfirst demonstration that progesterone-induced synthesis of\nlipid mediators derived from 12/15-LOX activity activated\nPPAR-g and associated signaling pathways, serving to regulate\nimplantation in the mouse. Indeed, LOX inhibitors have been\nshown to indirectly reduce progesterone output in pregnancy.\n40\nIt will be instructive to determine the relative roles of these\nintermediate metabolites and whether LXA\n4 is also involved.\nLXA4 RECEPTORS\nOf the LX family members, LXA 4 is the best characterized.\nLXA4 inhibits immune cell recruitment, chemotaxis, adhesion,\nand transmigration, also attenuating pro-inflammatory cyto-\nkine production and promoting resolution of inflammation,\nthereby serving as an important brake after injury or cellular\ninsult in vitro and in vivo. LXA\n4 modulates the function of both\nmyeloid and non-myeloid cell types. 41,42 This anti-inflamma-\ntory mediator appears promiscuous in its ability to bind and/or\nactivate a number of both nuclear as well as membrane-bound\nreceptors. LXA\n4 directly or indirectly activates various\nreceptors, including a subclass of peptide receptors (CysLTs\n(cysteinyl leukotrienes)), 15 as well as the G-protein-coupled\nreceptor 32. 43 LXA4 receptors also include formyl peptide\nreceptor 2/LX A 4 receptor (FPR2/ALX), another surface\nmembrane G-protein-coupled receptor with diverse\nligands,\n44,45 the aryl hydrocarbon receptor (AhR), a ligand-\nactivated nuclear transcription factor, 46 and more recently,\nestrogen receptor-alpha (ER a).28 Expression dynamics of the\nlatter three receptors and LXA 4 itself in endometrial tissue are\ndepicted in Figure 2 .\nFPR2/ALX, the most studied receptor, to which LXA 4 binds\nwith high affinity,44,45 is expressed by many different cell types,\nincluding neutrophils, monocytes, natural killer cells as well as\nepithelial cells, where its expression is subject to differential\nregulation by cytokines.\n23,47 A recent study on the molecular\nregulation of FPR2/ALX reported that although monocytes\nexpressed this receptor, their differentiation abrogated its\nexpression, due to translation silencing.48 These results suggest\nthat FPR2/ALX is of limited relevance in tissue macrophage\nREVIEW\n440 VOLUME 6 NUMBER 3 | MAY 2013 | www.nature.com/mi\n\nfunction, but further studies are required to delineate\nthe functional significance of this observation. Recently,\nexpression of FPR2/ALX in human endometrium has been\ndescribed.10 MacDonald et al. 10 found that FPR2/ALX\nmRNA expression is increased during the menstrual phase\ncompared with proliferative, early- and mid-secretory phase\nendometrium. As the endometrium has an upper (zona\nfunctionalis) and lower regenerative layer (zona basalis),\nFPR2/ALX receptor localization was found to be highest in\nthe functionalis layer, localized to glandular epithelial and\nstromal cells, as well as the cells lining the vasculature and\nassociated immune cells. We observed a smiliar expression\npattern (G. Canny, unpublished data). In the first trimester\nof pregnancy, the decidua also exhibits high FPR2/ALX\nexpression. Although LXA 4 levels did not change in the\nperipheral circulation across the menstrual cycle, serum levels\nwere increased during early pregnancy, coincident with\nelevated FPR2/ALX levels.\nAnother physiologically relevant receptor for LXA 4 is AhR,\nwhich LXA4 was shown to activate in murine hepatoma cells 46\nand murine dendritic cells. 49 Interestingly, AhR has a role in\nimmunity, with AhR-regulated genes being modulated by\nenvironmental toxins and pro-inflammatory cytokines. 50,51\nAhR-null mice succumb significantly faster to experimental\ntoxoplasmosis than wild-type mice and displayed greater\ndegrees of liver damage as well as augmented serum levels of\ntumor necrosis factor-alpha (TNF-a), nitric oxide, and IgE but\nlower IL-10 production. 52 Hematopoietic defects are also\nobserved in AhR /C0 / /C0 mice and, though classically considered\nimportant in mediating responses to environmental toxins,\nAhR is increasingly thought to be involved in immune\nresponses.53 Of note, cyclo-oxygenase 2 (COX-2), the rate\nlimiting enzyme in prostaglandin E 2 (PGE2) production is\ninducible by AhR ligands in various cell types.50 Although AhR\nis present in the human endometrium, where its expression\nremained constant across the menstrual cycle, 54 there have so\nFPR2/ALX\nAhR\nER-alpha\nZona\nFunctionalis\nZona\nBasalis\nEstrogen receptor - alpha\nMenses     Proliferative phase      Ovulation          Secretory phase\nLXA4\nLXA4\na\nb\nc\nESR1\nAhR\nFPR2/ALX\nFigure 2 Serum LXA 4 levels and receptor expression dynamics in\nendometrial tissue. (a) Lipoxin A4 (LXA4) activates multiple receptors and\nhas been shown to bind three present in the endometrium; formyl peptide\nreceptor 2/lipoxin A4 receptor (FPR2/ALX), a G-protein-coupled receptor,\naryl hydrocarbon receptor (AhR), a nuclear receptor, and estrogen\nreceptor-alpha (ESR1), which can exist in nuclear and membranous\nforms. (b) Each receptor appears to be differentially regulated, with FPR2/\nALX expressed with similar temporal dynamics to LXA 4. Serum LXA 4\nlevels have been reported (depicted by a green line), but no data\ndescribing endometrial tissue levels have been published. LXA4 also binds\nto estrogen receptor-alpha (ESR1), which increases in the proliferative\nphase in response to estrogen and later falls due to progesterone. AhR is\nconstitutively expressed throughout the menstrual cycle, but its functional\nsignificance is unclear. ( c) Immunohistochemical analyses of ESR1\nexpression during the secretory phase of the menstrual cycle in both\nthe zona functionalis (left upper panel) as well as the zona basalis\n(left lower panel). ESR1 is downregulated in the functionalis layer (right\nupper panel) but maintained in the zona basalis (right lower panel).\nAt menses, when estradiol levels are at their nadir, LXA 4 could target the\nnascent endometrial epithelium and stroma through ESR1 to promote\nearly proliferation and repair. Studies on both humans and primates have\nprovided evidence for cell division in this layer, despite the low\nendogenous estrogen levels. Thus, LXA4 may serve as an early signal for\nendometrial regeneration and renewal.\nEndometrium\nMenses\nNeutrophil\nMacrophage\nDecidua\nPregnancy\nuNK \nLXA\nEndometrial \ndecidual cell\nEndometriosis\nLXA\nEndometrium\nMacrophage\nPF\n4 4?AXL 4\nFigure 1 Lipoxin A 4 (LXA4)-mediated actions in the endometrium at\nmenses and in pregnancy on epithelial and stromal cells as well as on\nvarious immune cells of the innate arm. During menses, neutrophils and\nother immune cells are recruited just before menstruation and are normally\ncleared with debris, likely by macrophage-mediated efferocytosis, as a\nnew endometrial layer forms. LXA 4 is produced via transcellular\nbiosynthesis and 15-lipoxygenase is regulated by progesterone. In\npregnancy, LXA4 and its receptor appear to be upregulated, especially in\nthe decidua, a putative function of LXA 4 in this environment would be to\nmodulate macrophage activity and tissue remodeling. Elevated serum\nlevels during gestation may fulfill immunomodulatory roles. In\nendometriosis (middle panel), characterized by excessive estrogen\nproduction and progesterone resistance, LXA 4 levels have not been\nstudied. In this setting, LXA4 biosynthesis is possibly decreased leading to\na defect in the resolution of inflammation or alternatively, due to the\ninflammatory nature of this condition, may be overexpressed. The\nfunctional significance of LXA 4 in eutopic and ectopic endometrial tissue,\nas well as in the peritoneal fluid (PF), remains to be clarified. uNK, uterine\nnatural killer cell.\nREVIEW\nMucosalImmunology | VOLUME 6 NUMBER 3 | MAY 2013 441\n\nfar been no confirmatory reports demonstrating AhR activa-\ntion by LXA 4 in this tissue.\nLXA4 was recently characterized as an ER ligand, stimulating\nexpression of estrogen responsive genes, including alkaline\nphosphatase and PR, and inducing proliferation in human\nendometrial epithelial cells.28 Interestingly, LXA4 shares a high\ndegree of structural similarity with the weak estrogen estriol\n(E3) made in large amounts by the placenta during preg-\nnancy.\n55,56 Consistent with the characteristics of a weak ER a\nagonist, LXA 4 also inhibited E2-mediated actions, as was\npreviously shown for E3 57 and competed directly for ER\nbinding with an IC50 of 46 nM. Arachidonic acid and 15S-HETE,\nthe LX precursors, as well as LXB 4, an isomer, displayed\nminimal or no binding affinity, confirming the structural\nspecificity. Acting in a manner similar to canonical ER\nsignaling,\n58 LXA4 induced ER a phosphorylation and targeted\nthis receptor for degradation by the proteasome. Further\nconfirmatory studies in mice revealed that LXA\n4 stimulated a\nuterotrophic response and induced estrogen-responsive genes,\nincluding PR in uterine tissue in vivo .\nIt should be noted that all the three above-mentioned\nreceptors are promiscuous and subject to complex regulation in\nthe different endometrial cell types and at different stages of the\nmenstrual cycle or during gestation. Since multiple receptors\nmay be present in the same cell, well-controlled studies are\nneeded to fully explore potential crosstalk between these\ndifferent classes of receptors and associated signaling systems,\nusing physiologically relevant ligand concentrations and\nreadouts.\nALTERNATIVE VIEWS ON LXA 4 AND ESTROGEN ACTION\nThe endometrium is a steroid hormone–dependent tissue and,\nin the humans, undergoes cyclic changes in response to the\nsequential actions of estrogen and progesterone.\n59 Although the\nsteroid hormone and gene regulation patterns of the normal\nmenstrual cycle are beyond the scope of this review,\nendometrial changes have now been well characterized in\nboth health and disease.\n60–65 One of the major factors in\nendometrial-related diseases is the imbalance between the\nactions of estrogen and progesterone. Aside from the obvious\nexample of endometrial cancer, endometriosis is a major health\nproblem in women of reproductive age. The pathophysiology of\nendometriosis is intimately linked with inflammation, a\nresistance to progesterone, exaggerated estrogen responsive-\nness, and/or increased ER signaling.\n66\nEstrogen action in the endometrium in both health and\ndisease is an active area of research, and both estradiol and\nprogesterone regulate the inflammatory events during men-\nstruation and implantation.\n62,67 It has long been known that\nestrogen upregulates both ER a and PR in the human endo-\nmetrium68,69 as well as in primates and other mammals. 70\nLikewise, these studies have shown that progesterone down-\nregulates both ER a and PR during the secretory phase of the\ncycle.\n71 Early ER a immunohistochemistry data in human\nendometrium show that there is a marked reduction in all\nthe cell types during the mid-secretory phase.\n72–75 ER\ndownregulated in luminal and glandular epithelium was\nassociated with a decline in cell proliferation, except in the\nzona basalis.\n76,77 In pregnancy, ERa is essentially absent due to\nits down-modulation by progesterone. 78–82 Interestingly, the\ntimely loss of epithelial PR in the endometrium closely\ncorrelates well with the establishment of uterine receptivity\nin humans as well as in most mammals studied.\n81,83–88 A delay\nin the opening of the window of implantation is associated with\na correctable delay in the down-modulation of epithelial PR.\n89\nIt has been suggested that E2 is unnecessary for normal\nendometrial secretory development.\n90 Failure of ER a down-\nregulation could therefore, be an indirect sign of progesterone\nresistance and has been reported in endometrial hyperplasia, 75\nendometriosis,91–95 and in the endometrium of women with\npolycystic ovary syndrome. 64 Together, these data support the\nassociation between aberrant proliferation and the dysregula-\ntion of progesterone action, leading to proliferative disorders of\nthe endometrium and a lack of uterine receptivity.\nThe interactions between eicosanoids, lipoxygenase meta-\nbolites, estrogens and nuclear receptors have not been well\nstudied. E2 is the most potent estrogen produced in the body\nand like other estrogens exerts its physiological actions though\nbinding to and translocation of their receptors. ERs belong to\nthe nuclear hormone receptor superfamily and function as\nligand-activated transcription factors.\n96 Estrogen signaling is\nlargely mediated through two receptor isoforms: ERa and ERb,\ninitiating both genomic and non-genomic effects. 97 Both of\nthese ERs are abundant in reproductive tissues, ER a being the\ndominant receptor within the adult uterus98 and ERb of greater\nconcentration in vascular cells or of interest in reproductive\ntissues.\n74,99,100 Membrane ERs also exist, including the newly\ndiscovered G-protein-coupled receptor-30, recently studied in\nthe endometrium.\n101 Although studies using ER a-deficient\nmice have revealed the central role of this receptor in\nreproductive function at all levels of the hypothalamic–\npituitary–gonadal axis,\n102 ERb-mutant mice exhibit normal\npuberty but reduced fecundity due to an impaired ovulation\nrate.103 G-protein-coupled receptor 30 is dispensable for\nfertility and does not mediate estrogenic responses in mouse\nreproductive organs.\n104\nIn addition to ligand-induced activation, ERs are also subject\nto phosphorylation by various kinases that are themselves\nactivated by inflammatory mediators or cytokines during\nendometrial remodeling.\n105 TNFa was recently shown to\nactivate ER and induce E2-regulated genes in endometrial\nepithelial cells, 106 indicating immunoendocrine crosstalk\noccurs in inflammatory endometrial conditions. The signifi-\ncance of membrane-initiated steroid signaling\n107 in these\ncontexts remains to be elucidated, but alternations in the\ninflammatory milieu could dramatically alter the actions of\nestrogens, their metabolites, or other ligands, such as LXA\n4.\nA model of LXA 4-mediated actions in endometrial tissue\nwould depend on temporal and spatial availability of available\nligands and receptors ( Figure 2). The increased level of FPR2/\nALX at menses, 10 potentially coinciding with increased local\nLXA4 production due to immunocyte influx, 108 could\nREVIEW\n442 VOLUME 6 NUMBER 3 | MAY 2013 | www.nature.com/mi\n\ncontribute to the early burst of endometrial healing and growth\nthat occur at a time when endogenous E2 is relatively low. In\naddition, higher ERa expression noted in the basalis glands and\nstroma provides a potential target for LXA\n4 at menses when\nestrogen levels are at their nadir. Whether LXA 4 initiates\nendometrial regeneration and healing at this time merits\ninvestigation.\nThe zona basalis in primates undergoes cellular proliferation\nin the mid-to-late secretory phase.\n76,77 Given the reduced level\nof estrogen in the secretory phase and the virtual absence of ERa\nin endometrial epithelium and stroma of the zona functionalis\nat the time of implantation,\n73,74 it is possible that LXA 4 has a\nrole in that early proliferative activity seen in the basal glands,\nthought to be an important aspect of endometrial regeneration.\nERb, on the other hand, present in vascular components of the\nendometrium and placenta\n109 or FPR2/ALX, present in the\ndecidualized stroma, immune cells in the vasculature, and in\nthe myometrium of human uterus,\n10 may also be targets for\nLXA4 exerting anti-inflammatory actions to support the\nongoing pregnancy ( Figure 1 ). Pregnancy is, by necessity,\nan immunocompromised state, whereby the growing fetus is\ntolerated while maintaining maternal immunity. 110 LXA4,\nacting as an ER a agonist as previously observed in human\nendometrial epithelial cells, 28 may participate in the down-\nregulation of ER a observed in the late secretory phase. Loss of\nERa is also essential in the pre-implantation uterus of most\nmammalian species.\nFinally, AhR is a known receptor for LXA 4 and is present in\nthe endometrium of secretory endometrium. 54 Considering\nthe putative role of AhR as a suppressor of ER a signaling via\nseveral mechanisms, 111,112 it could be speculated that LXA 4\nmight come into play in certain circumstances. Although we\nshowed that AhR does not seem to be involved in LXA\n4\nsignaling in human endometrial epithelial cells, 28 actions\ninvolving this receptor in other cell types under different\ncircumstances or in vivo cannot be excluded.\nMACROPHAGES AS A LXA 4 TARGET\nInnate immune cells, including macrophages are a major target\nof LXA 4-mediated bioactivities ( Figure 1 ). Given that\nleukocytes represent 30–40% of the endometrial cell popula-\ntion\n113 leading to LXA 4 transcellular biosynthesis, this lipid\nmediator likely has a role in homeostatic processes. Macro-\nphages and uterine natural killer cells are abundant in the\nendometrial stroma and are found through most of the\nmenstrual cycle. Sex hormones regulate macrophage distribu-\ntion in this tissue. Macrophage numbers increase in the\npremenstrual endometrial stroma, coinciding with falling\nestrogen and progesterone levels due to the demise of the\ncorpus luteum.\n114\nMacrophages, through their ability to produce matrix\nmetalloproteinases (MMPs), are involved in tissue remodeling\nand are intimately linked with both menstruation108,113,115 and\npregnancy.116,117 It is noteworthy that LXA 4 and its analogs\ndecrease MMP expression and activity in many different\ncell types 118,119 and also in peritoneal fluid cells in a mouse\nmodel of endometriosis,120,121 of which macrophages comprise\na major component.\nIn the first trimester of pregnancy, macrophages constitute\nthe second most predominant leukocyte population (o30%) of\ndecidual cells after decidual natural killer cells ( o70%)122 and\ndifferentiate from monocytes. Decidual macrophages function\nin the removal of apoptotic bodies, uterine vascular remodeling,\nimmune tolerance towards fetal antigens, immunity against\nexternal pathogens and cervical ripening and recovery\n123 and\nelicit immunosuppressive and anti-inflammatory responses.\nApoptotic body clearance results in the expression of anti-\ninflammatory cytokines such as IL-4, IL-6, and IL-10, with\nprotective effects on trophoblast survival. Efferocytosis is a\nprocess whereby phagocytes engulf apoptotic cells and the latter\nimpact macrophage phenotype. The newly discovered pro-\nresolving macrophage subset, Mres, appear later in the\nresolution program.\n124 LXA4 promotes the engulfment of\napoptotic neutrophils, and tissue fragments, by macrophages, a\nprocess essential to the resolution of inflammation\n125,126 and\nthe re-establishment of tissue integrity post-menstruation. 113\nThe domains of immunology and metabolism are conver-\nging, providing insights into a variety of physiological and\npathological states.\n127 The previously mentioned ALOX\nmetabolites and PPAR ligands, as well as T helper type 2\n(Th2) cytokines and specialized pro-resolution mediators drive\ntemporarily distinct metabolic shifts and effector functions in\nmacrophages.\n128 Recent studies have implicated ER a in\nmacrophage function and metabolism and demonstrated a\nprotective role for this receptor on hematopoetic/myeloid cells\nin atherosclerosis-related inflammation.\n129 As alluded to above,\nestrogens are linked with macrophage recruitment into the\nendometrium and are clearly implicated in immune responses.\nThe role of ER a in LXA\n4-mediated regulation of macrophage\nfunction in the endometrium and peritoneal cavity awaits\nelucidation.\nENDOMETRIOSIS: A COMPLEX DISEASE FOR WHICH\nIMPROVED TREATMENT MODALITIES ARE NECESSARY\nEndometriosis, an inflammatory, estrogen-stimulated disease\naffects approximately 10% of women of reproductive age, and it\nis estimated that up to 80% of unexplained infertility is\nattributable to this condition.\n65,130,131 First described by Daniel\nSchroen in 1690, several theories have been proposed but none\nfully explain the etiology. The most well accepted is Samp-\nson’s\n132 theory of retrograde menstruation, whereby fragments\nof menstrual endometrium pass backward through the\nfallopian tubes and into the peritoneal cavity where they\nimplant and persist. The eutopic endometrium of women with\nendometriosis becomes altered as shown in the baboon\nmodel,\n133,134 with increased estrogen activity, cellular prolif-\neration, and progesterone resistance.66 The biological mechan-\nisms linking endometriotic lesions to these endometrial\nalterations remains uncertain and controversial. 135 Although\nprogesterone resistance and estrogen dominance likely con-\ntribute to the pathophysiology and survival of ectopic\nREVIEW\nMucosalImmunology | VOLUME 6 NUMBER 3 | MAY 2013 443\n\nlesions,134,136,137 they probably contribute to infertility as\nwell.66,95,134 There is overwhelming evidence that normal\nimmune responses, which serve to promote fertility and\nimmunotolerance, are altered in women with endometriosis,\nwith inflammatory changes in the intrauterine milieu, the\nperitoneal cavity, and systemic circulation.\n65,138–140\nCellular proliferation and inflammation are intimately\nlinked via both hormonal and inflammatory mediators such\nas IL-1, TNF- a, PGE\n2, or E2, which, in turn, induce growth\nfactors, cytokines, and chemokines that promote inflammation,\ncellular proliferation, and angio- and lymphangiogenesis.\n141,142\nEstrogens directly regulate the endometrial expression of many\ncytokines and growth factors as well as their receptors thereby\ncontributing to endometriotic lesion growth. 140 Conversely,\nTNF-a increases estrogen biosynthesis by human endometrial\nglandular cells and directs estrogen metabolism towards more\nhormonally active and carcinogenic metabolites.\n143 Crosstalk\nbetween the immune and endocrine systems therefore clearly\ncontributes to endometriosis pathology.\nDysregulations in local immune mediator concentration\nand/or signaling leads to increased inflammation in the\nperitoneal cavity and the resulting systemic changes could\nconceivably alter the number and profile of immune cells that\ntraffic to the endometrium. Dysfunction in macrophage-\nmediated phagocytosis of cells that are transported into the\nperitoneal cavity by retrograde menstruation is considered an\nimportant factor in the development of endometriosis. PGE\n2\ndiminished human macrophage-mediated phagocytosis by\ndownregulating the scavenger receptor and lipid transporter\nCD36, thought to have a significant role in macrophage-\nmediated phagocytosis, and also increased endometriotic lesion\nsize in mice.\n144 There is some evidence that macrophages in\nendometriosis are M2 polarized, also known as alternatively\nactivated macrophages, in human, mouse, and primate.\n145,146\nIn the former study, macrophages in both inflammatory liquid\nand ectopic lesions were M2 polarized in endometriosis\npatients but not in control subjects. Adoptive transfer of\nalternatively activated macrophages dramatically enhanced\nendometriotic lesion growth in mice, and M1 polarized,\ninflammatory macrophages protected mice from disease\nestablishment. It should be noted, however, that human\nmacrophages markers are less well characterized than murine\ncells and extracellular marker analysis should ideally be coupled\nwith that of pertinent effector molecules. Several different types\nof macrophages subsets have been described, and more are\nlikely yet to be discovered. Macrophages display a phenotypic\nplasticity as a function of environmental cues, including\ncytokines and growth factors.\n33 LXA4 promotes M2 polariza-\ntion in vitro.147 Further studies are necessary to determine the\nprecise macrophage subsets in endometrial tissue and peri-\ntoneal fluid and whether their polarization contributes to\npathological responses.\nIn endometriosis, establishment of an immunotolerant\n(Th2/Treg (regulatory T cell)) environment\n139,148,149 appears\nto be replaced by an inflammatory Th1/Th17 immune\nresponse.\n1,150 Retinoids, vitamin A derivatives that mediate\ndiverse physiological functions, exert their pleiotropic effects\nthrough the interaction with nuclear receptors, defined as\nretinoic acid receptors and retinoid X receptors (RXRs).\n151\nRetinoic acid (RA) as an important intermediary down-stream\neffector of progesterone action is also involved in immune cell\nprogramming.152 Retinol-binding proteins are under the\nregulation of progesterone in primates 153 and human endo-\nmetrium. Among six retinoid receptors examined, RXR g\nimmunoreactivity was exclusively detected in the epithelial cells\nof the secretory phase endometrium but not of the proliferative\nphase.\n154 These data indicate that its expression is induced by\nprogesterone. It is noteworthy that nuclear receptors such as\nRXR and PPAR- g heterodimerize and it seems that these\ndimers provide cells such as macrophages with a coordinated\nand inter-related network of transcriptional regulators for\ninterpreting local metabolic changes resulting in subtype\ndifferentiation.\n152 T-cell differentiation is altered toward an\ninflammatory phenotype in endometriosis, RA and PPAR- g\nbeing essential for Treg differentiation. 155,156 Inflammatory\nchanges, including augmented IL-6 and IL-23, promotes\nconversion of Tregs to Th17 cells. 157 Of note, PPAR- g\nselectively inhibits Th17 differentiation of CD4 þ T-cells.156\nAs such, several nuclear receptors likely impact physiological\nand pathological processes in endometrial tissue, conceivably\ninvolving LXA\n4.\nLXA4 inhibits endometriosis progression in the mouse\npreclinical model. 121,158 As shown for LXA 4 or a stable\nanalog,121,159 pretreatment with a combination of progester-\none, RA, and TGF b greatly attenuates MMPs expression and\nreduces endometriotic lesion growth. 160 Interestingly, LXA 4\nalso suppresses phorbol myristate acetate–induced expression\nof the inflammatory cytokines IL-6 and IL-8 in human decidua\ntissue\n10 and attenuates CCL2, IL-6 and inhibit nuclear factor\n(NF)-kB and Akt pathways in other animal models of inflam-\nmation.161,162 These observations may constitute mechanisms\nunderlying its beneficial effects in preclinical endometriosis\nmodels but also raise the question whether LXA 4 is a down-\nstream effector of progesterone and RA actions. Interestingly, a\nrecent paper demonstrated the protective effect of fish oil in\nendometriosis in a chimeric model where human endometrial\ntissue was injected into the peritoneum of nude mice.\n163 Mice\nadministered fish oil exhibited fewer leukocytes within lesions\nand less collagen deposition at adhesions indicating that dietary\nintervention may prevent postsurgical adhesion development.\nThese effects may well be due to the formation of pro-resolving\nlipid mediators such as resolvins and protectins, metabolized\nfrom omega 3 fatty acids.\n9\nHormone production, signaling, and metabolism are sig-\nnificantly perturbed and progesterone resistance comprises\npart of the pathology.\n66,164 Treatment of endometrial epithelial\ncells with 2,3,7,8-tetrachlorodibenzo -p-dioxin, a potent AhR\nligand, altered the expression of PR-B 165 as a possible\nmechanism of progesterone resistance, this environmental\ntoxin having been implicated in endometriosis development.\nPR-B in the uterus can exert an anti-inflammatory action,\nopposing PR-A.\n166 PR-A induced inflammatory cytokines\nREVIEW\n444 VOLUME 6 NUMBER 3 | MAY 2013 | www.nature.com/mi\n\nIL-8-, IL-1b-, and NF-kB-regulated genes, while PR-B induced\nFKBP52 and NFKB1A, an inhibitor of the NF- kB pathway.\nFKBP52 has been shown to be decreased in endo-\nmetriosis.\n167,168 This PR chaperone protein is required for\nproper progesterone-mediated actions and its reduction in\nthis disease may be a major determinant in progesterone\nresistance.\n136\nProgesterone resistance in endometriosis is associated with a\ndecrease in RA activity; 169 RA uptake protein STRA6 and\ncellular RA-binding protein 2 (both progesterone-regulated\ngenes) are reduced in eutopic endometrium in endometriosis.\nWomen with unexplained pregnancy loss also have reduced\nRA-binding protein 2.\n170 A recent study showed that RA\ntreatment reduced endometriosis lesion size in the mouse\nmodel, with decreased IL-6 and MCP-1,\n171 actions similar to\nthose elicited by LXA 4. RA acts in concert with progesterone\nand PPAR- g to limit inflammation; specifically inhibiting the\nexpression of the pleiotrophic cytokine IL-6 at the promoter,\nlimiting its production\n172 along with IFN- g, while reduced\nRA action results in augmented IL-6 expression. 169 In\nendometriosis, stromal cells produce increased IL-6 in response\nto IL-1 b.173\nEstrogen’s ability to inhibit LXA 4 production in other\nmucosal tissues 35 has important potential implications for\nendometriosis. As progesterone opposes estrogen action,\nprogesterone resistance leads to increased estrogenicity in\neutopic and ectopic endometrial tissue, perhaps also in the\nperitoneal compartment. ERa itself is one of the best recognized\nmarkers of progesterone resistance. In endometriosis, ER a is\nmore abundant and displays a failure of downregulation in\neutopic\n95 and ectopic tissue. 174,175 The underlying reasons are\nunknown but could include aberrant modification and/or\ntargeting to the proteasome, as part of abnormal responses to\nthis hormone, or could be linked to progesterone resistance.\nERa is more important than ER b in endometriosis lesion\ndevelopment in mice, as recently demonstrated in an\nimmunocompetent model.\n176 In this study, ER a-null lesions\nwere associated with increased inflammation, it is therefore\ntempting to speculate that endogenous ER a ligands mediate\nthis effect.\nHowever, data from human studies showed that ER b is\noverexpressed in endometriotic lesions and may have a role in\nthe pathophysiology. A high ER b-to-ERa ratio in endome-\ntriotic stromal cells is associated with suppressed PR and\naugmented COX-2 levels contributing to progesterone resis-\ntance and inflammation.\n100 High levels of ER b result in\nsuppressed ER a expression and estradiol responses in endo-\nmetrial and endometriotic stromal cells. 174 We have recently\ndemonstrated increased ER a and ER b expression in ectopic\nand peritoneal tissue of patients with peritoneal endometriosis\ncompared with control subjects, with a particularly marked\nelevation in ER b observed,\n175 as has also been reported for\novarian endometriosis. 164 The respective role of stromal and\nepithelial cells within lesions as well as the myeloid cells in the\nperitoneal cavity, and their immune and metabolic products,\nremains unclear. ER crosstalk and regulation is likely to be\ncrucial. This complex area of biology necessitates further\nresearch and differences between murine models and the\nhuman pathology likely exist. Advances in understanding\nof the latter will necessitate standardized, well-designed studies\nand facilitate the discovery of relevant biomarker panels, which\nwill hopefully serve to decrease the long delay before\ndiagnosis.\n177–179\nEstrogen production is also increased in endometriosis, 180\nlikely influenced by the inflammatory environment. 181 Here,\nthe COX-2-derived eicosanoid PGE 2, as a potent inducer of\naromatase and Steroidogenic acute regulatory protein expres-\nsion, has a pivotal role.\n182 Furthermore, estrogen degradation is\nregulated by progesterone and defective in progesterone\nresistance.183 Estrogen may be pro-inflammatory in endome-\ntriosis184 and contributes to the pathophysiology of the disease\nas a mitogen causing aberrant proliferation185 and inhibition of\napoptosis,186 decreasing the tumor-suppressor phosphatase\nand tensin homolog deleted on chromosome 10 via NF- kB\ndependent pathways. 187\nDefective immunity and decreased production or activity of\nanti-inflammatory mediators such as LXA 4 could account for\nthe development of sustained inflammation seen in the\nreproductive tract and peritoneal fluid\n188 of endometriosis\npatients. Alterations in endometrial stroma have long been\nnoted,\n173,189 including an exaggerated response to IL-1 b and\nTNF-a, resulting in excessive production of the inflammatory\ncytokines ENA-78 (epithelial neutrophil–activating peptide-\n78), IL-6, and IL-8.\n190 Other inflammatory cytokines, including\nIL-17, increase IL-8 secretion and expression of COX-2 191 and\naromatase,192,193 making this pathway an attractive therapeutic\ntarget.194 LXA4 production is induced by IL-13 in monocytes,30\nand IL-13 is regulated during the menstrual cycle, with\nexpression induced by ovarian steroid hormones and cyto-\nkines.\n39,195 Studies on micro(mi)RNA expression 196,197 have\nrevealed a wide variety of changes in this disease. Let-7 miRNA\nwas one of those most upregulated in the endometrium of\nwomen with endometriosis\n196 and intruigingly, a let-7 miRNA\npolymorphism has been associated with endometriosis. 198\nLet-7 miRNAs inhibit IL-13 expression. 199\nCurrent treatments are directed toward surgical excision of\nectopic endometrial tissue, and symptom alleviation, usually by\ntargeting hormones or their receptors. Upon cessation of\ntreatment, endometriosis frequently recurs. Furthermore,\nsurgery can result in adhesion development, which can also\nlead to chronic pelvic pain and infertility.\n200 Novel approaches\nare therefore necessary as traditional therapies, the majority of\nwhich target hormones or their receptors, have been hampered\nby poor bioavailability, undesirable side effects, and a negative\nimpact on fertility.\n201,202 As inflammation underlies the major\nendometriosis-associated symptoms, notably infertility and\npain, a well-tolerated immunomodulatory therapy targeting\ninflammatory changes associated with this disease could\nimprove symptoms without the untoward side-effects of\nexisting treatments. As detailed above, LXA\n4 exerts a protective\neffect in preclinical endometriosis models, through anti-\ninflammatory and anti-angiogenic mechanisms.\n120,121,159\nREVIEW\nMucosalImmunology | VOLUME 6 NUMBER 3 | MAY 2013 445\n\nImportantly, cycling remained unchanged, indicating that\nLXA4 does not alter ovarian function.\nIn conclusion, complex and interrelated pathways link the\nimmune response to steroid hormone actions. Studies on\nendometrial function and endometriosis confirm the impor-\ntance of the balance between inflammation and its resolution.\nPregnancy itself is dependent on this compromise between\nself-defense and beneficence.\n110 Future research efforts\nwill be needed to clarify the functional ramifications of\nLXA\n4 as an anti-inflammatory modulator and ER agonist.\nAs a molecule with multiple modes of action and the ability to\nmitigate some E2-mediated responses,\n28 as well as potentially\ndivergent actions on myeloid and non-myeloid cell types,\nrevelations on its role in endometrial physiology and meta-\nbolism will likely identify therapeutic opportunities. Indeed,\nresearch in the emerging domain of immuno-metabolism\nis predicted to generate key insights into reproductive biology\nand disease.\nACKNOWLEDGEMENTS\nStudies described here were funded by the Swiss National Science\nFoundation (grant number 310030-12076), Roche and Novartis Research\nFoundations as well as by the Department of Gynecology and Obstetrics,\nCentre Hospitalier Universitaire Vaudois (to GOC) and by the NIH\nR01HD067721 (to BAL).\nDISCLOSURE\nThe authors declare no conflict of interest.\n& 2013 Society for Mucosal Immunology\nREFERENCES\n1. Guerin, L.R., Prins, J.R. & Robertson, S.A. Regulatory T-cells and immune\ntolerance in pregnancy: a new target for infertility treatment?. Hum.\nReprod. Update 15, 517–535 (2009).\n2. Evans, J. & Salamonsen, L.A. Inflammation, leukocytes and menstrua-\ntion. Rev. Endocr. Metab. Disord. 13, 277–288 (2012).\n3. Jabbour, H.N., Sales, K.J., Catalano, R.D. & Norman, J.E. 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The molecular mechanisms underlying\nthe pharmacological actions of ER modulators: implications for\nnew drug discovery in breast cancer. Curr. Opin. Pharmacol. 10,\n620–628 (2010).\nREVIEW\n450 VOLUME 6 NUMBER 3 | MAY 2013 | www.nature.com/mi","source_license":"CC0","license_restricted":false}