Abstract
Asthma is a common inflammatory disease of the airway caused by a combination of genetic and environmental factors and characterized by airflow obstruction, wheezing, eosinophilia, and neutrophilia of lungs and sputum. Similar to other proinflammatory cytokines, IL-6 is elevated in asthma and plays an active role in this disease. However, the exact molecular mechanism of IL-6 involvement in the pathogenesis of asthma remains largely unknown and the major cellular source of pathogenic IL-6 has not been defined. In the present study, we used conditional gene targeting to demonstrate that macrophages and dendritic cells are the critical sources of pathogenic IL-6 in acute HDM-induced asthma in mice. Complete genetic inactivation of IL-6 ameliorated the disease with significant decrease in eosinophilia in the lungs. Specific ablation of IL-6 in macrophages reduced key indicators of type 2 allergic inflammation, including eosinophil and Th2 cell accumulation in the lungs, production of IgE and expression of asthma-associated inflammatory mediators. In contrast, mice with deficiency of IL-6 in dendritic cells demonstrated attenuated neutrophilic, but regular eosinophilic response in HDM-induced asthma. Taken together, our results indicate that IL-6 plays a pathogenic role in the HDM-induced asthma model and that lung macrophages and dendritic cells are the predominant sources of pathogenic IL-6 but contribute differently to the disease.
Highlights
Allergic asthma is a chronic inflammatory disease of the airways that occurs in response to inhaled allergens, such as pollen, house dust mites, and fungi
IL-6 was implicated in the pathogenesis of allergic asthma both in human patients and in several mouse models of asthma [11, 24, 25], the contribution of this cytokine in the most clinically relevant mouse model—administration of house dust mite (HDM) at low doses—has not been addressed
These results are in accordance with earlier findings that IL-6 may enhance airway hyper responsiveness, allergic inflammation and development of airway remodeling in the high dose HDM-induced asthma model [24]
Summary
Allergic asthma is a chronic inflammatory disease of the airways that occurs in response to inhaled allergens, such as pollen, house dust mites, and fungi. The incidence and the severity of chronic lung diseases, such as allergic asthma, are growing and affect between 200 and 300 million people worldwide. It is associated with a significant mortality rate [1]. Asthma is characterized by swelling and narrowing of the airways, infiltration of eosinophils to the lungs and activation of Th2 cells [2]. The initial cause that triggers most chronic and acute lung diseases remains unknown, and currently available therapies only ameliorate the symptoms, but do not cure the disease. There is a pressing need to identify new targets and develop novel therapies, especially, for those most severely affected
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