Estrogen Promotes Resolution of Pneumonia via CD4+Foxp3+ Tregs

Abstract

Pneumonia (PNA) is one of the leading causes of death worldwide. Current treatments for PNA are focused on the pathogens (e.g. vaccinations and antibiotics), but don't target excessive lung inflammation elicited by the host immune response; underscoring the need to identify additional therapeutic targets in PNA. Clinical and experimental evidence exists for sex differences in PNA outcomes and survival, with males having higher mortality. In contrast to studying early events (i.e., risk of infection and transmission), our work focuses on active immunoregulatory pathways that promote resolution of inflammation and lung repair with the ultimate goal to improve PNA‐ALI outcomes. Recognizing the critical role of Regulatory T cells (Tregs) in resolution of lung injury, we predict that improved PNA outcomes in females are the result of sex differences in Treg biology. We cultured Tregs and stimulated them with E2, our data showed exogenous estradiol (E2) promoted Treg suppressive phenotype and proliferation in vitro. We challenged male and female wild‐type mice with intratracheal Streptococcus pneumoniae to make murine model of PNA during early and resolution phases. Despite similar early lung injury, resolution was delayed in male mice compared to female while displaying increased lung CD4+Foxp3+ Tregs. To determine therapeutic effects of E2 on resolution, we rescued male mice 2 days after PNA with systemic administration of E2. Comparing with vehicle administrated mice, male mice after systemic administration of E2 had increased Tregs. The therapeutic effects of E2 were Treg‐dependent as Treg‐depleted (diphtheria toxin‐treated Foxp3DTR) mice did not resolve their injury in response to estrogen. Our results showed that estrogen augments Treg number and function to accelerate repair experimental PNA‐induced lung injury. Estrogen represents novel treatment for PNA by enhancing the host immune system.Support or Funding InformationR01 Franco D'AlessioThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.