The Role of Ovarian Hormones and Testosterone on Type 2 and Il-17a-Mediated Airway Inflammation

Severe asthma is a significant health care concern, with patients having poorer asthma control, poorer lung function, and increased health care costs compared to milder asthma phenotypes. A sexual dimorphism also exists in severe asthma, and as adults, women are twice as likely as men to have severe asthma. Increased type 2 cytokines and/or IL-17A, leading to increased airway eosinophil and neutrophils, respectively, are associated with asthma. Previous studies showed that ovarian hormones increased while testosterone decreased type 2 OR IL-17A-mediated inflammatory responses. However, the mechanisms by which sex hormones mediated dual type 2 cytokines and IL-17A inflammatory responses remained unclear. We hypothesized that during dual type 2 and IL-17A mediated airway inflammation, ovarian hormones promote inflammation by increasing cytokine expression of type 2 cytokines and IL-17A while testosterone attenuates inflammation by decreasing cell numbers of type 2 and IL-17A secreting cells. To test our hypothesis, we utilized a house dust mite (HDM) model of airway inflammation in hormonally intact or deficient female and male mice and determined how sex hormones affected total numbers and cytokine expression from CD4+ T helper cell subsets important for type 2 inflammation (Th2 cells) or IL-17A-mediated inflammation (Th17 cells). Ovarian hormones increased and testosterone decreased HDM-induced IL-13+Th2 cells and IL-17A+ Th17 cells, but through different mechanisms. Subsequent studies using ERα and AR deficient mice determined that ERα signaling increased IL-23R surface expression on Th17 cells, leading to increased IL-17A protein expression. However, AR signaling intrinsically decreased total numbers of IL-17A+ Th17 cells in the lung and decreased Il23r mRNA and IL-17A protein expression in Th17 cells. Combined, these findings showed that sex hormones signaling regulates type 2 and IL-17A-mediated airway inflammation and IL-17A expression in Th17 cells, providing potential mechanisms for the increased prevalence of asthma in women compared to men

Testosterone Attenuates Group 2 Innate Lymphoid Cell-Mediated 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, 5α-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

CD4+ T cells expressing CX3CR1, GPR56, with variable CD57 are associated with cardiometabolic diseases in persons with HIV.

Persons with HIV (PWH) on long-term antiretroviral therapy (ART) have a higher incidence and prevalence of cardiometabolic diseases attributed, in part, to persistent inflammation despite viral suppression. In addition to traditional risk factors, immune responses to co-infections such as cytomegalovirus (CMV) may play an unappreciated role in cardiometabolic comorbidities and offer new potential therapeutic targets in a subgroup of individuals. We assessed the relationship of CX3CR1+, GPR56+, and CD57+/- T cells (termed CGC+) with comorbid conditions in a cohort of 134 PWH co-infected with CMV on long-term ART. We found that PWH with cardiometabolic diseases (non-alcoholic fatty liver disease, calcified coronary arteries, or diabetes) had higher circulating CGC+CD4+ T cells compared to metabolically healthy PWH. The traditional risk factor most correlated with CGC+CD4+ T cell frequency was fasting blood glucose, as well as starch/sucrose metabolites. While unstimulated CGC+CD4+ T cells, like other memory T cells, depend on oxidative phosphorylation for energy, they exhibited higher expression of carnitine palmitoyl transferase 1A compared to other CD4+ T cell subsets, suggesting a potentially greater capacity for fatty acid β-oxidation. Lastly, we show that CMV-specific T cells against multiple viral epitopes are predominantly CGC+. Together, this study suggests that among PWH, CGC+ CD4+ T cells are frequently CMV-specific and are associated with diabetes, coronary arterial calcium, and non-alcoholic fatty liver disease. Future studies should assess whether anti-CMV therapies could reduce cardiometabolic disease risk in some individuals