Leptin augments IL-13-induced airway eotaxins and submucosal eosinophilia in obesity-associated asthma.

Abstract

BackgroundAirway tissue eosinophilia can be an observed feature of obesity-associated type 2 (T2) asthma, but the processes mediating this inflammation are unknown.ObjectiveTo investigate a process whereby leptin, an adipokine elevated in obesity, potentiates pulmonary eosinophilia and eotaxin production by airway fibroblasts in T2 asthma.MethodsWe assessed associations between body mass index and airway eosinophilia as well as leptin and eotaxin production in 82 participants with asthma, 37 of whom exhibited obesity. Cultured human airway fibroblasts and mouse models of chronic allergic airway disease were used to evaluate leptin's effect on eotaxin production and lung eosinophilia. The role of IL-13 receptor alpha 2 (IL-13Rα2) in mediating these processes was examined using specific neutralizing antibodies in vitro.ResultsIn participants with T2 asthma and obesity, we observed that airway tissue eosinophilia did not associate with traditional T2 inflammation metrics such as peripheral and/or bronchoalveolar lavage fluid eosinophil counts or with fractional exhaled nitric oxide. Alternatively, we observed elevated bronchoalveolar lavage fluid leptin and eotaxin-1 levels. In airway fibroblasts from participants with asthma, leptin augmented IL-13-induced eotaxin-1 and eotaxin-3 production and IL13RA2 expression. In mice, elevated leptin promoted airway IL-13Rα2 and eotaxin production by lung fibroblasts and lung tissue eosinophilia following chronic house dust mite allergen exposure. Inhibition of IL-13Rα2 reduced combined leptin and IL-13-stimulated eotaxin secretion by human airway fibroblasts.ConclusionsWe identified a potential association explaining airway tissue eosinophil retention in obesity-associated T2 asthma through leptin-mediated enhancement of IL-13-induced eosinophil chemokine production by airway fibroblasts, a process requiring IL-13Rα2.