JCI Insight. 2021 Feb 8;6(3):133251. doi: 10.1172/jci.insight.133251.
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.
目前肺炎（PNA）的治疗方法侧重于病原体。由 PNA 引起的急性肺损伤（PNA-ALI）的死亡率仍然很高，这突显了需要额外的治疗靶点。临床和实验证据表明，PNA 存活存在潜在的性别差异，男性死亡率更高。在严重肺炎球菌性 PNA 的模型中，与雄性小鼠相比，年龄匹配的雌性小鼠表现出增强的消退特征，表现为肺泡和肺部炎症减少，Treg 数量增加。认识到 Treg 在肺损伤消退中的关键作用，我们评估了雌性小鼠中改善的结果是否归因于雌二醇（E2）对 Treg 生物学的影响。E2 在体外促进 Treg 抑制表型，并在体内解决 PNA。E2 的全身挽救性给药促进了雄性小鼠中 PNA 的消退，而不依赖于肺部细菌清除。E2 增强了 Treg 表达 Foxp3、CD25 和 GATA3，这种作用需要 ERβ，而不是 ERα 信号。重要的是，E2 的体内治疗效果在 Treg 耗竭小鼠（Foxp3DTR 小鼠）中丧失。体外用 E2 处理的 Treg 的过继转移挽救了肺炎链球菌诱导的 PNA-ALI，这种有益作用需要 Treg ERβ 表达。E2/ERβ 是 Treg 控制巨噬细胞促炎反应所必需的。我们的研究结果支持 E2 通过 ERβ Treg 促进 PNA 后肺炎症消退的治疗作用。
