Androgens inhibit IL-33 production and airway inflammation

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Severe asthma patients have a high morbidity and utilize >50% of asthma-related health care each year. IL-33 signaling through its receptor, ST2 (IL1RL1), drives allergic airway inflammation, airway hyperresponsiveness, and mucus production by increasing IL-4, IL-5, and IL-13 production from Th2, group 2 innate lymphoid cells (ILC2), and other cells types. While anti-IL-33 is a promising asthma therapeutic, additional understanding of pathways the regulate this pathway could lead to novel therapeutic options in this patient population. In the previous funding period, we determined how ovarian hormones increased IL-17A and type 2-mediated airway inflammation in severe asthma, which is most common in women. Through the course of these studies we also found that that androgen receptor (AR) signaling attenuated Th17 cell differentiation, ILC2 proliferation, and allergic airway inflammation. Gonadectomized male mice (which lack androgens) also had increased Alt Ext-induced IL-33 compared to hormonally intact male mice. Yet, the mechanisms by which AR signaling attenuates allergen-induced airway inflammation were unclear. Androgens signaling through the AR are associated with increased lung function and decreased asthma symptom scores in women and men with asthma. New preliminary data for this application suggest that AR signaling decreases allergic airway inflammation by decreasing the release of active IL-33, sustaining T regulatory cells (Tregs) stability and suppressive function, and decreasing ST2 expression on Th2 and ILC2 cells to limit IL-33-mediated allergic airway inflammation. We hypothesize that AR signaling post- transcriptionally modifies IL-33 to limit release, restrains downstream IL-33 signaling by inhibiting ST2 expression and signaling, and stabilizes Treg suppressive function. To test this hypothesis, we will use primary, differentiated bronchial epithelial cell and immune cells from the excised lungs and lymph nodes of women and men with asthma as well as mouse models of asthma to: Aim 1) Determine the mechanisms by which AR signaling limits IL-33 release from human bronchial epithelial cells, Aim 2) Delineate how AR signaling potentiates Treg stability and suppressive function during allergic airway inflammation, and Aim 3) Determine if AR signaling decreases ST2 expression and downstream signaling on Th2 cells to reduce allergic airway inflammation. Delineating how AR signaling attenuates IL-33 release while maintaining lung Treg function will be critical for personalizing therapies for women and men with severe asthma and potentially other IL-33-mediated diseases.