Activation of the annexin A1 pathway underlies the protective effects exerted by estrogen in polymorphonuclear leukocytes.

OBJECTIVE The anti-inflammatory properties of the female sex hormone estrogen have been linked to a reduced incidence of cardiovascular disease. In the present study, we addressed whether estrogen could activate vasculoprotective mechanisms via annexin A1 (AnxA1) mobilization in human polymorphonuclear cells (PMNs). METHODS AND RESULTS Using whole-blood flow cytometry, we demonstrated that premenopausal women expressed higher levels of surface AnxA1 on circulating PMNs compared with males. This correlated with high plasma estrogen during the menstrual cycle. The addition of estrogen in vitro to male PMNs induced rapid mobilization of AnxA1, optimal at 5 ng/mL and a 30-minute incubation period; this effect was abolished in the presence of the estrogen receptor antagonist ICI182780. Estrogen addition to human PMNs induced a distinct AnxA1(hi) CD62L(lo) CD11b(lo) phenotype, and this was associated with lower cell activation as measured by microparticle formation. Treatment of human PMNs with E(2) inhibited cell adhesion to an endothelial cell monolayer under shear, which was absent when endogenous AnxA1 was neutralized. Of interest, addition of estrogen to PMNs flowed over the endothelial monolayer amplified its upregulation of AnxA1 localization on the cell surface. Finally, in a model of intravital microscopy, estrogen inhibition of white blood cell adhesion to the postcapillary venule was absent in mice nullified for AnxA1. CONCLUSION We unveil a novel AnxA1-dependent mechanism behind the inhibitory properties of estrogen on PMN activation, describing a novel phenotype with a conceivable impact on the vasculoprotective effects of this hormone.