Mechanisms by which Obesity Dysregulates Immunometabolic State in Asthma

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Childhood asthma and obesity are two of the most common chronic diseases worldwide. As body mass increases, there is an increase in asthma prevalence, supporting a possible pathophysiological link. While the mechanism of that link remains unclear, immunometabolic dysfunction is increasingly appreciated as a key mechanism in immunological disease and hereperwe tested that hypothesis. Prospective immunometabolic study of pediatric asthma and obesity with recruitment of obese asthmatics (OA), non-obese asthmatics (A), obese non-asthmatics (O) and healthy controls (HC). Asthmatics were recruited from our Allergy clinic with deep clinical metadata. To assess the underlying mechanisms of immune dysfunction, we used peripheral blood mass cytometry (CyTOF), flow cytometry, serum metabolomics and cytokine analysis and high dimensional systems immunology analytics. A second cohort of asthmatics (OA and A) was assessed as well. Human in vitro culture of PBMCs and a mouse model of obese asthma were then used to test hypothesized mechanisms of T cell dysfunction from these studies. Pediatric atopic OA demonstrated alterations in T cell differentiation including increased type 2 immunity and T cell exhaustion. OA also demonstrated altered serum metabolites including glutamate and acetate, which were shown to underlie some of the immune dysfunction using in vitro and in vivo studies. We have identified novel insights into the mechanistic links between metabolic disturbances and immune dysfunction in obesity and asthma. We are further extending mechanistic testing in mouse models of obese asthma and in vitro in human studies to move towards identification of novel therapeutic strategies targeting these mechanisms.