The role of lipoxin A4 in endometrial biology and endometriosis

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.

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

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 LXA_4. 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.