Annexin A1/Formyl Peptide Receptor Pathway Controls Uterine Receptivity to the Blastocyst

Abstract

Embryo implantation into the uterine wall is a highly modulated, complex process. We previously demonstrated that Annexin A1 (AnxA1), which is a protein secreted by epithelial and inflammatory cells in the uterine microenvironment, controls embryo implantation in vivo. Here, we decipher the effects of recombinant AnxA1 in this phenomenon by using human trophoblast cell (BeWo) spheroids and uterine epithelial cells (Ishikawa; IK). AnxA1-treated IK cells demonstrated greater levels of spheroid adherence and upregulation of the tight junction molecules claudin-1 and zona occludens-1, as well as the glycoprotein mucin-1 (Muc-1). The latter effect of AnxA1 was not mediated through IL-6 secreted from IK cells, a known inducer of Muc-1 expression. Rather, these effects of AnxA1 involved activation of the formyl peptide receptors FPR1 and FPR2, as pharmacological blockade of FPR1 or FPR1/FPR2 abrogated such responses. The downstream actions of AnxA1 were mediated through the ERK1/2 phosphorylation pathway and F-actin polymerization in IK cells, as blockade of ERK1/2 phosphorylation reversed AnxA1-induced Muc-1 and claudin-1 expression. Moreover, FPR2 activation by AnxA1 induced vascular endothelial growth factor (VEGF) secretion by IK cells, and the supernatant of AnxA1-treated IK cells evoked angiogenesis in vitro. In conclusion, these data highlight the role of the AnxA1/FPR1/FPR2 pathway in uterine epithelial control of blastocyst implantation.

A proteome signature for acute incisional pain in dorsal root ganglia of mice

“…Anxa1 (formerly known as lipocortin-1) has originally been identified as a mediator of anti-inflammatory actions of glucocorticoids. 10 , 18 , 33 , 42 It has further been shown to act through MAPK/ERK signaling endorsing our network prediction analysis (Fig. 5 ).…”

“…Rather, IPA-based network analysis (Fig. 5 ) identified potential upstream modulators of ERK signaling such as complement component 3 (C3), fibrinogen A/B/G (Fga, Fgb, Fgg), and Annexin1 (Anxa1), 33 none of which have so far been described in the context of incisional pain (Supplemental Digital Content 2: results of our literature search, available at http://links.lww.com/PAIN/B274 ). Using immunolabeling, we focused specifically on Anxa1.…”

Maternal RNF114-mediated target substrate degradation regulates zygotic genome activation in mouse embryos

“…Some proteins in the Annexin family were also identified, including ANXA1, ANXA2, ANXA3 and ANXA11. These proteins are mainly reported to be related to embryo implantation and postimplantation development (Hebeda et al, 2018(Hebeda et al, , 2020; Kultima et al, 2004; Meadows and Cleaver, 2015;Wang and Shao, 2020). To date, no evidence supports their relationship to the MZT process.…”

Pro-Resolving Mediator Annexin A1 Regulates Intracellular Ca2+ and Mucin Secretion in Cultured Goblet Cells Suggesting a New Use in Inflammatory Conjunctival Diseases

“…Using ALX/FPR2, AnxA1 functions to resolve diverse inflammatory events, including reduction of joint injury in experimental arthritis ( 39 ), lessening of salivary gland inflammation ( 40 ), and contributes to corneal wound healing ( 41 ). AnxA1 in uterine epithelial cells also activates the ALX/FPR2 receptor to upregulate the membrane-spanning mucin MUC1, tight junction molecules claudin-1 and occludens 1 to increase adherence of trophoblast steroids, a model for embryo implantation ( 42 ). Herein we showed that AnxA1 activates the ALX/FPR2 receptor in rat conjunctival goblet cells and that this activation leads to the increase in [Ca 2+ ] i and secretion of mucins into the tear film.…”