Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A...

Area of Science:

• Immunology
• Endocrinology
• Respiratory Medicine

Background:

• Women exhibit a higher prevalence of severe asthma compared to men.
• Interleukin-17A (IL-17A) is implicated in severe asthma pathogenesis.
• IL-17A production is dependent on IL-23 receptor (IL-23R) signaling, which is negatively regulated by let-7f microRNA.

Purpose of the Study:

• To elucidate the mechanism by which 17β-estradiol (E2) and progesterone (P4) enhance IL-17A production.
• To investigate the role of sex hormones in regulating IL-17A and IL-23R expression in severe asthma.

Main Methods:

• Flow cytometry was used to measure IL-17A production in TH17 cells from male and female patients with severe asthma.
• Quantitative PCR assessed IL-23R and let-7f expression in TH17-differentiated cells from healthy men and women.
• Hormone administration and adoptive transfer models in mice were employed to study IL-17A regulation and airway inflammation.

Main Results:

• TH17 cells from women with severe asthma produced higher levels of IL-17A compared to men.
• Increased IL-23R expression and decreased let-7f expression were observed in TH17 cells from women.
• Administration of 17β-estradiol and progesterone (17β-E2+P4) to female mice increased IL-17A and IL-23R expression and decreased let-7f expression in TH17 cells.
• Transfer of female-derived TH17 cells led to greater neutrophil infiltration in mouse lungs compared to male-derived TH17 cells.

Conclusions:

• The combination of 17β-estradiol and progesterone (17β-E2+P4) enhances IL-17A production by TH17 cells.
• This hormonal mechanism offers a potential explanation for the higher incidence of severe asthma in women.
• Findings highlight the role of sex hormones in modulating immune responses relevant to severe asthma.