Obesity lowers the threshold of allergic sensitization and augments airway eosinophilia in a mouse model of asthma.

BACKGROUND: Clinical and epidemiological studies show a close association between obesity and the risk of asthma development. The underlying cause-effect relationship between metabolism, innate and adaptive immunity, and inflammation remains to be elucidated. METHODS: We developed an animal model to study the interaction between metabolic abnormalities and experimentally induced asthma. Obesity-susceptible AKR mice were fed with high-fat diet (HFD) or normal low-fat diet (LFD) and subjected to a protocol of ovalbumin (OVA) sensitization and airway allergen challenges followed by assessment of inflammation and lung function. RESULTS: AKR mice developed obesity and a prestage of metabolic syndrome following HFD. This phenotype was associated with an increase in proinflammatory macrophages (CD11b+/CD11c+) together with higher serum levels of interleukin 6. Obese mice showed increased susceptibility to allergic sensitization as compared to LFD animals. Anti-ovalbumin IgE antibody titers correlated positively and anti-OVA IgG2a antibodies titers correlated negatively with body weight. Airway eosinophilia showed a positive correlation with body weight, whereas mucus production did not change with obesity. CONCLUSIONS: This obesity model demonstrates that HFD-induced obesity lowers the sensitization threshold in a model of asthma. This finding helps to understand why, particularly during childhood, obesity is a risk factor for the development of allergic asthma.

Clara cells drive eosinophil accumulation in allergic asthma.

Development of allergic asthma is a complex process involving immune, neuronal and tissue cells. In the lung, Clara cells represent a major part of the "immunomodulatory barrier" of the airway epithelium. To understand the contribution of these cells to the inflammatory outcome of asthma, disease development was assessed using an adjuvant-free ovalbumin model. Mice were sensitised with subcutaneous injections of 10 µg endotoxin-free ovalbumin in conjunction with naphthalene-induced Clara cell depletion. Clara epithelial cell depletion in the lung strongly reduced eosinophil influx, which correlated with decreased eotaxin levels and, moreover, diminished the T-helper cell type 2 inflammatory response, including interleukin (IL)-4, IL-5 and IL-13. In contrast, airway hyperresponsiveness was increased. Further investigation revealed Clara cells as the principal source of eotaxin in the lung. These findings are the first to show that Clara airway epithelial cells substantially contribute to the infiltration of eotaxin-responsive CCR3+ immune cells and augment the allergic immune response in the lung. The present study identifies Clara cells as a potential therapeutic target in inflammatory lung diseases such as allergic asthma.