Estriol Reduces Pulmonary Immune Cell Recruitment and Inflammation to Protect Female Mice From Severe Influenza

Abstract

Estriol (E3) is an endogenous estrogen in females with broad biological activity within diverse tissue types. In the context of certain T-cell-mediated autoimmune inflammatory diseases, E3 can ameliorate disease severity through immunomodulatory mechanisms that decrease tissue inflammation. Severe disease caused by influenza A virus (IAV) infection is also characterized by aberrant inflammation and immunopathology. How E3 might affect the pathogenesis of IAV infection, however, has not been explored. Gonadally intact female C57BL/6 mice that were treated with exogenous E3 during infection with mouse-adapted 2009 H1N1 had reduced total pulmonary inflammation and improved disease outcomes compared with females that received no hormone. Furthermore, compared with no hormone treatment, E3 treatment reduced the induction of genes associated with proinflammatory cytokine and chemokine responses in the lungs, which preceded clinical disease, reductions in innate immune cell recruitment, altered pulmonary T-cell skewing, and reduced antibody titers during IAV infection. Although E3 treatment was associated with reduced local and systemic anti-influenza adaptive immune responses, there was no effect of E3 on viral replication or clearance. Together, these data suggest that exogenous E3 confers protection during IAV infection through immunomodulatory mechanisms and that E3 may have broad therapeutic potential in the context of both infectious and noninfectious inflammatory diseases.

Androgen receptor signaling in the lungs mitigates inflammation and improves the outcome of influenza in mice

“…Testosterone can be metabolized in tissues, converted into estradiol, and signal through estrogen receptors (ERs) [45]. Estradiol signaling through ERα can dampen inflammation and improve the outcome of IAV infection, at least in female mice [21,46,47]. To determine whether the protective effects of testosterone during IAV infection in male mice were caused by signaling through AR or ER, male mice were gonadectomized and implanted with capsules containing either testosterone, placebo, or a combination of testosterone and the AR antagonist, flutamide [48].…”

Biological sex influences susceptibility to Acinetobacter baumannii pneumonia in mice

“…However, sex-based differences and the host immune mechanisms behind this differential response have only recently begun to be dissected. Several studies have presented data showing differential immune response to infectious diseases according to sex (14)(15)(16). The innate immune response of females is typically stronger in the context of infection (12).…”

Artificial intelligence-based CT metrics in relation with clinical outcome of COVID-19 in young and middle-aged adults

“…Many studies had reported the relationship between estrogen and immune system in antiviral response. One study had indicated that the diffuse alveolar damage in severe influenza was correlated with excessive inflammation, while estradiol was an effective anti-inflammatory hormone that relieved the severity of influenza A virus infection in women [13]. It can recruit more neutrophils to improve the reaction of influenza virus-specific CD8 + T cells for releasing more IFN-γ and TNF-α.…”

“…We found that men had more extensive and larger volume of GGO in bilateral lungs while women showed less volume but denser lesions in bilateral lower lobes. Estrogen may help the immune system detect and confront the virus in an early stage [13], which could restrict the infection within the originally preferred regions. Regarding a larger percentage of consolidation in women on initial CT, the lesions may progress into a relatively late stage due to the longer days from illness onset to admission, compared to men.…”