Estrogen negatively regulates epithelial wound healing and protective lipid mediator circuits in the cornea

Abstract

Estrogen receptors (ERs) are expressed in leukocytes and in every ocular tissue. However, sex-specific differences and the role of estradiol in ocular inflammatory-reparative responses are not well understood. We found that female mice exhibited delayed corneal epithelial wound closure and attenuated polymorphonuclear (PMN) leukocyte responses, a phenotype recapitulated by estradiol treatment both in vivo (topically in male mice) and in vitro (corneal epithelial cell wound healing). The cornea expresses 15-lipoxygenase (15-LOX) and receptors for lipoxin A(4) (LXA(4)), which have been implicated in an intrinsic lipid circuit that regulates corneal inflammation and wound healing. Delayed epithelial wound healing correlated with lower expression of 15-LOX in the regenerated epithelium of female mice. Estradiol in vitro and in vivo down-regulated epithelial 15-LOX expression and LXA(4) formation, while estradiol abrogation of epithelial wound healing was completely reversed by treatment with LXA(4). More important, ERβ and ERα selectively regulated epithelial wound healing, PMN cell recruitment, and activity of the intrinsic 15-LOX/LXA(4) circuit. Our results demonstrate for the first time a sex-specific difference in the corneal reparative response, which is mediated by ERβ and ERα selective regulation of the epithelial and PMN 15-LOX/LXA(4) circuit. These findings may provide novel insights into the etiology of sex-specific ocular inflammatory diseases.

Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair

“…In this report, we demonstrate a beneficial role of FPR signaling in mediating ANXA1-induced epithelial ROS generation that exerts a novel pro-resolution function in vivo. Our study demonstrating the importance of FPR signaling in promoting epithelial wound closure supports previous reports by Gronert et al (68)(69)(70). These studies highlighted a critical role of another pro-resolving FPR2 ligand, LXA4, in facilitating recovery of corneal epithelial wounds.…”

“…Topical treatment with LXA4 not only accelerated wound closure, but also attenuated chemokine release. Furthermore, LXA4-dependent protective effects were sex specific, as estradiol was able to downregulate LXA4 formation (68).…”

Lipoxin A4-mediated KATP potassium channel activation results in cystic fibrosis airway epithelial repair

“…Although it has not been shown in CF before, our results indicating that LXA 4 stimulates airway epithelial wound repair of CF airway epithelial cell line and primary cultures are consistent with the role of this lipid mediator in the resolution of inflammation. This work is supportive of its effects previously reported in corneal epithelial and airway epithelial repair after an acid injury (3,20,40,47). The effect of LXA 4 on CF airway epithelial wound healing appeared to involve stimulation of cell migration and cell proliferation.…”

Cofactors of LIM Domains Associate with Estrogen Receptor α to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function

“…Estrogen receptors are expressed in all ocular surface tissues, including the cornea. This is interesting as a recent study highlighted the sex-specific differences in corneal wound healing (41).…”