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Developmental biology - Female Hormones|
Why do more women have asthma than men?
"When we started this study, we really thought that ovarian hormones would increase inflammation, more so than testosterone making it better. I was surprised to see that testosterone was more important in reducing inflammation."
Prior studies found that before puberty, boys have approximately 1.5 times higher rates of asthma than girls (Journal of Allergy and Clinical Immunology). That trend reverses after puberty, when women are twice as likely to have asthma as men. A pattern that continues until women hit menopause, when asthma rates in women start to decline. Increased asthma symptoms are regulated by many different factors such as exposure to allergens and viral infections, but researchers suspected sex hormones might also be involved.
Newcomb and her colleagues studied human and mouse cells to follow gender differences they had observed. They focused on lung cells called Group 2 innate lymphoid cells, or ILC2 cells. These cells make cytokines which are proteins that cause inflammation and mucus production in the lungs. Mucus makes it harder to breathe. Researchers collected blood from people with and without asthma finding that those with asthma had more ILC2 cells than those without. Of that group, asthmatic women had more ILC2 cells than asthmatic men.
ILC2 cells make up only about 10,000 of the 10 million cells in a mouse lung. Similar to results found in humans. Newcomb and colleagues always found fewer cells from male mice than female mice. They used these mouse cells to experiment with the effects of hormones on ILC2 cells.
When researchers added ovarian estrogen and progesterone to ILC2 cells, not much changed or increased these cells' ability to make cytokines. But, when testosterone was added, it prevented cells from expanding, reducing the production of cytokines - thus reducing inflamation.
While this study focused on testosterone, Newcomb hopes to expand further studies to explore the effects of more sex hormones on asthma.
Newcomb: "Sex hormones are not the only mechanism but, rather, one of many mechanisms that could be regulating airway inflammation. This is not the only important mechanism in asthma."
• The number of ILC2 is increased in women with asthma compared to men with asthma
• Sex hormones regulate IL-2-dependent ILC2 proliferation and cytokine expression
• Testosterone intrinsically and extrinsically attenuates ILC2 airway inflammation
Sex hormones regulate many autoimmune and inflammatory diseases, including asthma. As adults, asthma prevalence is 2-fold greater in women compared to men. The number of group 2 innate lymphoid cells (ILC2) is increased in patients with asthma, and we investigate how testosterone attenuates ILC2 function. In patients with moderate to severe asthma, we determine that women have an increased number of circulating ILC2 compared to men. ILC2 from adult female mice have increased IL-2-mediated ILC2 proliferation versus ILC2 from adult male mice, as well as pre-pubescent females and males. Further, 5?-dihydrotestosterone, a hormone downstream of testosterone, decreases lung ILC2 numbers and IL-5 and IL-13 expression from ILC2. In vivo, testosterone attenuated Alternaria-extract-induced IL-5+ and IL-13+ ILC2 numbers and lung eosinophils by intrinsically decreasing lung ILC2 numbers, as well as by decreasing expression of IL-33 and thymic stromal lymphopoietin (TSLP), ILC2-stimulating cytokines. Collectively, these findings provide a foundational understanding of sexual dimorphism in ILC2 function.
Authors: Jacqueline-Yvonne Cephus, Matthew T. Stier, Hubaida Fuseini, Jeffrey A. Yung, Shinji Toki, Melissa H. Bloodworth, Weisong Zhou, Kasia Goleniewska, Jian Zhang, Sarah L. Garon, Robert G. Hamilton, Vasiliy V. Poloshukin, Kelli L. Boyd, R. Stokes Peebles Jr., Dawn C. Newcomb
This work was supported by the National Institute of Health and the Veteran Affairs.
Cell Reports (@CellReports), published by Cell Press, is a weekly open-access journal that publishes high-quality papers across the entire life sciences spectrum. The journal features reports, articles, and resources that provide new biological insights, are thought-provoking, and/or are examples of cutting-edge research. Visit: http://www.cell.com/cell-reports. To receive Cell Press media alerts, contact email@example.com.
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The Number of Circulating ILC2 Is Increased in Women with Asthma Compared to Men with Asthma.
(A–C) Blood was collected from men and women with moderate to severe asthma and from healthy controls. (A) Representative dot plots from a woman and a man with asthma show flow cytometry gating strategy for circulating ILC2, defined as Lin-, CD45+, CD127+, CD161+, CD25+, and CRTH2+ cells. (B) The number of ILC2 as a percentage of PBMCs per milliliter of blood. (C) Representative histograms of Gata3+ ILC2 from a woman with asthma (red outline) compared to a man with asthma (blue outline); gray peak represents isotype control.