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

Abstract

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.

Biological sex influences susceptibility to Acinetobacter baumannii pneumonia in mice

“…Consistent with our observations, female mice intranasally infected with P. aeruginosa have increased rates of mortality and levels of inflammatory cytokines, in addition to increased neutrophil necrosis (15). We observed that depletion of neutrophils led to increased bacterial burdens in our study irrespective of sex, so the observed increase in neutrophil necrosis in females both in our study and Abid et al (15) is a likely reason behind the sex bias. Why this is not observed in other bacterial respiratory models in mice could be due to differences in animal models and humans.…”

“…Direct evidence as to how the hormones influence these conditions is not fully known. While our own respiratory studies with Staphylococcus aureus, Klebsiella pneumoniae, or Streptococcus pneumoniae (46)(47)(48)(49) have not indicated a significant susceptibility for any particular sex in mouse models, it has been shown that female mice are more susceptible to respiratory Pseudomonas aeruginosa infection (15). Consistent with our observations, female mice intranasally infected with P. aeruginosa have increased rates of mortality and levels of inflammatory cytokines, in addition to increased neutrophil necrosis (15).…”

“…While our own respiratory studies with Staphylococcus aureus, Klebsiella pneumoniae, or Streptococcus pneumoniae (46)(47)(48)(49) have not indicated a significant susceptibility for any particular sex in mouse models, it has been shown that female mice are more susceptible to respiratory Pseudomonas aeruginosa infection (15). Consistent with our observations, female mice intranasally infected with P. aeruginosa have increased rates of mortality and levels of inflammatory cytokines, in addition to increased neutrophil necrosis (15). We observed that depletion of neutrophils led to increased bacterial burdens in our study irrespective of sex, so the observed increase in neutrophil necrosis in females both in our study and Abid et al (15) is a likely reason behind the sex bias.…”

“…However, sex-based differences and the host immune mechanisms behind this differential response have only recently begun to be dissected. Several studies have presented data showing differential immune response to infectious diseases according to sex (14)(15)(16). The innate immune response of females is typically stronger in the context of infection (12).…”

‘Go for it, dream big, work hard and persist’: A message to the next generation of CF leaders in recognition of International Women's Day 2020

“…Our wide-ranging experiences of how these are dealt with around the world can identify areas to be addressed. The gender-gap in CF survival, a concept discussed frequently in the medical literature [1][2][3][4][5][6][7][8] , is considered visible in many of our regions, is incompletely understood and requires further research.…”