Obesity and estrogen signaling upregulate Th17 cell metabolism in asthma

Obese women have the highest prevalence of severe, uncontrolled asthma leading to increased asthma- related morbidity, exacerbations, and health care costs.1 New therapeutic options are critically needed for patients, particularly obese women, with severe asthma. Asthma is not a uniform disease with mild to severe phenotypes that is driven by increase airway inflammation, mucus production, and airway hyperreactivity. Milder phenotypes of asthma have increased airway eosinophils and CD4+ Th2 cell cytokine production where more severe phenotypes of asthma, that do not respond well to corticosteroids, have increased airway neutrophils and IL17-producing T cells (Th17). T cell metabolism plays a critical role to in T cell differentiation and inflammation, thereby influencing airway inflammation in asthma. Dr. Rathmell’s laboratory (co-I on this application) showed glutamine metabolism is critical for Th17 cell differentiation and allergen-induced airway inflammation in a mouse model. Glutamine is metabolized to glutamate by glutaminase (GLS), and GLS inhibition with CB839 impaired development of Th17 cells and protected against lung inflammation in a mouse model of neutrophilic asthma. Preliminary data for this application showed 1) patients with severe asthma have increased Th17 cells and glutamine metabolism compared to healthy controls, 2) Women with severe asthma have increased Th17 cells compared to men with severe asthma, 3) high fat diet (HFD, 45%) fed female, but not male, mice had increased frequencies of Th17 cells, and 4) 17β-estrogen signaling through estrogen receptor alpha (ER-α) increased Th17 cell differentiation, IL-17A production, and Th17 cell metabolism. However, it remains unclear if ER-α signaling and obesity alter T cell glutamine metabolism for preferential differentiation of Th17 cells and IL-17A production. Based on these data, we hypothesize that obesity and ER-α signaling increase glutamine metabolism in activated T cells, leading to increased Th17 cell differentiation and IL-17A production in severe asthma.

To test our hypothesis, we have assembled an impressive team of experts and utilize many of Vanderbilt University Medical Center’s core facilities and propose the following aims:
Aim 1: Test if T cells from healthy and severe asthma human donors that are normal weight or obese have different regulation of glutamine metabolism that may be targeted.
Aim 2: Determine if ER-α signaling enhances glutamine metabolism in T cells in obese female mice.