Estradiol resolves pneumonia via ERβ in regulatory T cells

Current treatments for pneumonia (PNA) are focused on the pathogens. Mortality from PNA-induced acute lung injury (PNA-ALI) remains high, underscoring the need for additional therapeutic targets. Clinical and experimental evidence exists for potential sex differences in PNA survival, with males having higher mortality. In a model of severe pneumococcal PNA, when compared with male mice, age-matched female mice exhibited enhanced resolution characterized by decreased alveolar and lung inflammation and increased numbers of Tregs. Recognizing the critical role of Tregs in lung injury resolution, we evaluated whether improved outcomes in female mice were due to estradiol (E2) effects on Treg biology. E2 promoted a Treg-suppressive phenotype in vitro and resolution of PNA in vivo. Systemic rescue administration of E2 promoted resolution of PNA in male mice independent of lung bacterial clearance. E2 augmented Treg expression of Foxp3, 01325, and GATA3, an effect that required ER beta, and not ER alpha, signaling. Importantly, the in vivo therapeutic effects of E2 were lost in Treg-depleted mice (Foxp3(DTR) mice). Adoptive transfer of ex vivo E2-treated Tregs rescued Streptococcus pneumoniae-induce PNA-ALI, a salutary effect that required Treg ER beta expression. E2/ER beta was required for Tregs to control macrophage proinflammatory responses. Our findings support the therapeutic role for E2 in promoting resolution of lung inflammation after PNA via ER beta Tregs.

Automated summary

Current treatments for pneumonia primarily target the pathogens, but mortality from pneumonia-induced acute lung injury remains high, highlighting the need for additional therapeutic targets. Evidence suggests potential sex differences in pneumonia survival, with females showing enhanced resolution in severe pneumonia models. Estradiol promotes Treg-mediated resolution of pneumonia via ER beta signaling, with therapeutic effects observed in both male and female mice. The findings support a potential therapeutic role for estradiol in modulating lung inflammation resolution after pneumonia.