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 havi...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-02-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.133251 |
| _version_ | 1819111239435943936 |
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| author | Ye Xiong Qiong Zhong Tsvi Palmer Alison Benner Lan Wang Karthik Suresh Rachel Damico Franco R. D’Alessio |
| author_facet | Ye Xiong Qiong Zhong Tsvi Palmer Alison Benner Lan Wang Karthik Suresh Rachel Damico Franco R. D’Alessio |
| author_sort | Ye Xiong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T03:54:27Z |
| format | Article |
| id | doaj.art-799e16b8da674ef0882b711b253315d2 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-22T03:54:27Z |
| publishDate | 2021-02-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-799e16b8da674ef0882b711b253315d22022-12-21T18:39:54ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-02-0163Estradiol resolves pneumonia via ERβ in regulatory T cellsYe XiongQiong ZhongTsvi PalmerAlison BennerLan WangKarthik SureshRachel DamicoFranco R. D’AlessioCurrent 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.https://doi.org/10.1172/jci.insight.133251ImmunologyPulmonology |
| spellingShingle | Ye Xiong Qiong Zhong Tsvi Palmer Alison Benner Lan Wang Karthik Suresh Rachel Damico Franco R. D’Alessio Estradiol resolves pneumonia via ERβ in regulatory T cells JCI Insight Immunology Pulmonology |
| title | Estradiol resolves pneumonia via ERβ in regulatory T cells |
| title_full | Estradiol resolves pneumonia via ERβ in regulatory T cells |
| title_fullStr | Estradiol resolves pneumonia via ERβ in regulatory T cells |
| title_full_unstemmed | Estradiol resolves pneumonia via ERβ in regulatory T cells |
| title_short | Estradiol resolves pneumonia via ERβ in regulatory T cells |
| title_sort | estradiol resolves pneumonia via erβ in regulatory t cells |
| topic | Immunology Pulmonology |
| url | https://doi.org/10.1172/jci.insight.133251 |
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