Less Airway Inflammation and Goblet Cell Metaplasia in an IL-33-Induced Asthma Model of Leptin-Deficient Obese Mice

Abstract BackgroundAsthma with obesity is a phenotype of severe asthma. Leptin exerts an immunomodulatory effect and its level is increased in obesity. IL-33 is associated with innate immunity and induces type 2 inflammation, and is present in adipose tissue. However, the role of IL-33 and leptin in obesity-associated asthma is not fully understood. We examined the effect of IL-33 on eosinophilic inflammation, goblet cell metaplasia, and airway responsiveness in leptin-deficient obese (ob/ob) and wild-type mice, and examined the effect of exogenous leptin pretreatment. MethodsIn ob/ob and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the animals, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine and resistance of the respiratory system (Rrs) was measured using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, KC in bronchoalveolar lavage fluid (BALF), and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin, and MUC5AC levels were measured by ELISA. ResultsOb/ob mice showed greater baseline Rrs than wild-type mice. IL-33 and IL-33 with leptin did not enhance Rrs challenged with methacholine compared to non-treatment in ob/ob mice, whereas IL-33 with leptin enhanced Rrs in wild-type mice. Ob/ob mice showed less IL-33-induced eosinophil numbers, IL-5, IL-13, eotaxin, and KC levels in BALF and eosinophilic infiltration around bronchi and goblet cell metaplasia than wild-type mice, but leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro . ConclusionsLeptin plays an important role in IL-33-induced inflammation and goblet cell metaplasia in the airway, but obesity per se increases airway hyperresponsiveness independent of inflammation. These results explain some aspects of the pathogenesis of obesity-related asthma.