Estradiol resolves pneumonia via ERβ in regulatory T cells.

Ye Xiong,Tsvi Palmer,Alison Benner,Karthik Suresh,Franco R D’Alessio,Qiong Zhong,Rachel Damico,Lan Wang

doi:10.1172/jci.insight.133251

Abstract

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, CD25, and GATA3, an effect that required ERβ, and not ERα, signaling. Importantly, the in vivo therapeutic effects of E2 were lost in Treg-depleted mice (Foxp3DTR mice). Adoptive transfer of ex vivo E2-treated Tregs rescued Streptococcus pneumoniae–induce PNA-ALI, a salutary effect that required Treg ERβ expression. E2/ERβ 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 ERβ Tregs.

Highlights

Pneumonia (PNA) is one of the leading causes of death worldwide, resulting in an estimated 2.74 million deaths [1]
Given prior reports showing increased forkhead box protein 3 (Foxp3) expression and suppressive function effect by E2 on Tregs [36], a cell type we previously showed to be important for acute lung injury (ALI) resolution [29], we hypothesized that resolution of PNA would be enhanced in female mice in vivo
While lung inflammation was largely cleared by 6 days after PNA-induced acute lung injury (PNA-ALI) in female mice, male mice experienced sustained weight loss (Figure 1A) and a higher number of bronchoalveolar lavage (BAL) total cells (Figure 1C), with predominance of neutrophils (Figure 1D)

Summary

Introduction

Pneumonia (PNA) is one of the leading causes of death worldwide, resulting in an estimated 2.74 million deaths [1]. Current treatments for ALI/ARDS caused by PNA are focused primarily on pathogen killing with antibiotics but do not target excessive lung inflammation elicited by the host immune response [3]. Treg numbers in both the BAL and lung were increased in female mice in the resolution phase of PNA. Exogenous systemic administration of E2 given as rescue treatment 48 hours after lung infection promoted resolution of PNA-ALI in male mice with decreased lung inflammation, decreased BAL inflammatory cytokines, and increased the number of lung Tregs. This was independent of effects on lung bacterial burden. Our results provide support of estrogenic mechanisms involved in PNA-ALI resolution, identifying new targets regulating Treg function and therapeutics that enhance Treg prorepair function

Results

Discussion

Methods