Effects of androgen receptor (AR) signaling on CD4+ T cell metabolism during airway inflammation

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PROJECT SUMMARY/ABSTRACT Severe asthma is difficult to control and accounts for the majority of asthma-related healthcare costs and hospitalizations. Consistent with patterns of asthma, severe asthma rates are higher in women than men. Severe, uncontrolled asthmatics may have airway inflammation mediated by a type 2, eosinophilic immune response or may have increased neutrophilic driven airway inflammation driving by IL-17A and/or IFN-. Testosterone, which signals through the androgen receptor (AR), decreases airway inflammation in mice. Nebulized dehydroepiandrosterone-3-sulfate (DHEA-S), an androgen, improved asthma control in moderate to severe asthma patients in a Phase II randomized clinical trial. However, the mechanisms by which AR signaling decreases Th2 and Th17 driven airway inflammation in asthma remains unclear. My labs showed that AR signaling decreased Th2 and Th17 driven inflammation and increased Treg stability in mice, that men with severe asthma have significantly decreased circulating Th17 cells compared to women with severe asthma, and that CD4+ T helper cells have distinct modes of metabolism, with Th17 and Th2 relying on glutaminolysis and glycolysis metabolism and Tregs relying on oxidative phosphorylation. Further, my labs previously showed increased glutaminolysis and glycolysis in bronchoalveolar lavage fluid from patients with asthma and circulating T cells from patients with severe asthma had increased expression of markers of glutaminolysis and glycolysis. My preliminary data shows that AR signaling decreases metabolic function through reductions in glutaminolysis and glycolysis in mouse Th2 and Th17 cells. Additionally, male mice with house dust mite (HDM) induced airway inflammation have decreased expression of enzymes related to glutaminolysis compared to female mice. Recent studies showed that the let7 microRNA family reduced glycolytic and glutaminolytic processes in B cells and CD8 T cells. Let7f, a member of the let7f miRNA family, downregulated IL-17A and IL-23R expression in Th17, and our lab showed that ovarian hormones decreased and 5α-DHT, an androgen, increased let7f expression in Th17 cells. Therefore, metabolic changes in T cells could explain the change in the inflammatory milieu seen in severe, uncontrolled asthma. Based on these findings, I hypothesize that AR signaling decreases glutaminolysis and glycolysis in T helper cells, resulting in decreased Th2 and Th17-mediated airway inflammation. In this proposal, I will: (1) determine how AR signaling decreases metabolism of T helper cells to limit airway inflammation, and (2) elucidate how AR signaling promotes the negative regulation of let7f on T helper cell metabolism and differentiation. These studies will demonstrate fundamental mechanisms by which sex hormones regulate CD4+ T cell biology as well as uncover and provide evidence for new potential therapeutics, including DHEA-S or metabolic inhibitors such as CB839, for patients with uncontrolled severe asthma using innovative techniques in immunometabolism.