17β-Estradiol Dysregulates Innate Immune Responses to Pseudomonas Aeruginosa Respiratory Infection and Is Modulated by Estrogen Receptor Antagonism

Females have a more severe clinical course than males in terms of several inflammatory lung conditions. Notably, females with cystic fibrosis (CF) suffer worse outcomes, particularly in the setting of infection. Sex hormones have been implicated in experimental and clinical studies; however, immune mechanisms responsible for this sex-based disparity are unknown and the specific sex hormone target for therapeutic manipulation has not been identified. The objective of this study was to assess mechanisms behind the impact of female sex hormones on host immune responses to We used wild-type and CF mice, which we hormone manipulated, inoculated with , and then examined for outcomes and inflammatory responses. Neutrophils isolated from mice and human subjects were tested for responses to We found that female mice inoculated with died earlier and showed slower bacterial clearance than males ( < 0.0001). Ovariectomized females supplemented with 17β-estradiol succumbed to challenge earlier than progesterone- or vehicle-supplemented mice ( = 0.0003). 17β-Estradiol-treated ovariectomized female mice demonstrated increased lung levels of inflammatory cytokines, and when rendered neutropenic the mortality difference was abrogated. Neutrophils treated with 17β-estradiol demonstrated an enhanced oxidative burst but decreased killing and earlier cell necrosis. The estrogen receptor (ER) antagonist ICI 182,780 improved survival in female mice infected with and restored neutrophil function. We concluded that ER antagonism rescues estrogen-mediated neutrophil dysfunction and improves survival in response to ER-mediated processes may explain the sex-based mortality gap in CF and other inflammatory lung illnesses, and the ER blockade represents a rational therapeutic strategy.