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Review
.2013 May;6(3):439-50.
doi: 10.1038/mi.2013.9. Epub 2013 Mar 13.

The role of lipoxin A4 in endometrial biology and endometriosis

Affiliations
Review

The role of lipoxin A4 in endometrial biology and endometriosis

G O Canny et al. Mucosal Immunol.2013 May.

Abstract

Lipoxin A4 (LXA4), an endogenous anti-inflammatory and immunomodulatory mediator studied in many disease states, is recently appreciated as a potentially significant player in the endometrium. This eicosanoid, synthesized from arachidonic acid via the action of lipoxygenase enzymes, is likely regulated in endometrial tissue during the menstrual cycle. Recent studies revealed that LXA4 acts as an estrogen receptor agonist in endometrial epithelial cells, antagonizing some estrogen-mediated activities in a manner similar to the weak estrogen estriol, with which it shares structural similarity. LXA4 may also be an anti-inflammatory molecule in the endometrium, though its precise function in various physiological and pathological scenarios remains to be determined. The expression patterns for LXA4 and its receptor in the female reproductive tract suggest a role in pregnancy. The present review provides an oversight of its known and putative roles in the context of immuno-endocrine crosstalk. Endometriosis, a common inflammatory condition and a major cause of infertility and pain, is currently treated by surgery or anti-hormone therapies that are contraceptive and associated with undesirable side effects. LXA4 may represent a potential therapeutic and further research to elucidate its function in endometrial tissue and the peritoneal cavity will undoubtedly provide valuable insights.

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Figures

Figure 1
Figure 1
Lipoxin A4 (LXA4)-mediated actions in the endometrium at menses and in pregnancy on epithelial and stromal cells as well as on various immune cells of the innate arm. During menses, neutrophils and other immune cells are recruited just before menstruation and are normally cleared with debris, likely by macrophage-mediated efferocytosis, as a new endometrial layer forms. LXA4 is produced via transcellular biosynthesis and 15-lipoxygenase is regulated by progesterone. In pregnancy, LXA4 and its receptor appear to be upregulated, especially in the decidua, a putative function of LXA4 in this environment would be to modulate macrophage activity and tissue remodeling. Elevated serum levels during gestation may fulfill immunomodulatory roles. In endometriosis (middle panel), characterized by excessive estrogen production and progesterone resistance, LXA4 levels have not been studied. In this setting, LXA4 biosynthesis is possibly decreased leading to a defect in the resolution of inflammation or alternatively, due to the inflammatory nature of this condition, may be overexpressed. The functional significance of LXA4 in eutopic and ectopic endometrial tissue, as well as in the peritoneal fluid (PF), remains to be clarified. uNK, uterine natural killer cell.
Figure 2
Figure 2
Serum LXA4 levels and receptor expression dynamics in endometrial tissue. (a) Lipoxin A4 (LXA4) activates multiple receptors and has been shown to bind three present in the endometrium; formyl peptide receptor 2/lipoxin A4 receptor (FPR2/ALX), a G-protein-coupled receptor, aryl hydrocarbon receptor (AhR), a nuclear receptor, and estrogen receptor-alpha (ESR1), which can exist in nuclear and membranous forms. (b) Each receptor appears to be differentially regulated, with FPR2/ALX expressed with similar temporal dynamics to LXA4. Serum LXA4 levels have been reported (depicted by a green line), but no data describing endometrial tissue levels have been published. LXA4 also binds to estrogen receptor-alpha (ESR1), which increases in the proliferative phase in response to estrogen and later falls due to progesterone. AhR is constitutively expressed throughout the menstrual cycle, but its functional significance is unclear. (c) Immunohistochemical analyses of ESR1 expression during the secretory phase of the menstrual cycle in both the zona functionalis (left upper panel) as well as the zona basalis (left lower panel). ESR1 is downregulated in the functionalis layer (right upper panel) but maintained in the zona basalis (right lower panel). At menses, when estradiol levels are at their nadir, LXA4 could target the nascent endometrial epithelium and stroma through ESR1 to promote early proliferation and repair. Studies on both humans and primates have provided evidence for cell division in this layer, despite the low endogenous estrogen levels. Thus, LXA4 may serve as an early signal for endometrial regeneration and renewal.
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