Abstract
BackgroundDetermining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies. Although elevated IL-6 and polymorphisms in IL-6 signalling are associated with lung dysfunction in asthma, it remains unknown if elevated IL-6 levels are associated with a specific cellular inflammatory phenotype, and how IL-6 blockade might impact such inflammatory responses.MethodsPatients undergoing exacerbations of asthma were phenotyped according to their airway inflammatory characteristics (normal cell count, eosinophilic, neutrophilic, mixed granulocytic), sputum cytokine profiles, and lung function. Mice were exposed to the common allergen, house dust-mite (HDM), in the presence or absence of endogenous IL-6. The intensity and nature of lung inflammation, and levels of pro-granulocytic cytokines and chemokines under these conditions were analyzed.ResultsElevated IL-6 was associated with a lower FEV1 in patients with mixed eosinophilic-neutrophilic bronchitis. In mice, allergen exposure increased lung IL-6 and IL-6 was produced by dendritic cells and alveolar macrophages. Loss-of-function of IL-6 signalling (knockout or antibody-mediated neutralization) abrogated elevations of eosinophil and neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice.ConclusionsWe demonstrate the association of pleiotropic cellular airway inflammation with IL-6 using human and animal data. These data suggest that exacerbations of asthma, particularly those with a combined eosinophilic and neutrophilic bronchitis, may respond to therapies targeting the IL-6 pathway and therefore, provide a rational basis for initiation of clinical trials to evaluate this.
Highlights
Determining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies
Using Luminex bead-based multiplex immunoassay of dithiothreitol (DTT)-treated sputum supernatants, we found significantly higher levels of IL-6 in patients with asthma with a mixed eosinophilic and neutrophilic bronchitis compared to patients with asthma with an isolated eosinophilic or intense neutrophilic bronchitis or normal cell counts (Figure 1)
Clinical data show that IL-6/IL-6R is differentially expressed in asthmatics versus healthy controls, and that this is associated with airway dysfunction [6]
Summary
Determining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies. Asthma is a chronic disease of the airways characterized by reversible airflow obstruction, airway hyperresponsiveness, and airway inflammation While these are disease defining features, asthma has more recently been recognized as a widely heterogeneous disease with multiple clinical variants, subtypes depending on factors such as severity, responsiveness to corticosteroids, or nature of airway inflammation. Recent genome-wide association studies have identified polymorphisms in IL-6R as novel asthma risk loci that correlate with lower percent predicted FEV1, forced vital capacity (FVC) and FEV1/FVC ratio [10,12]. Such polymorphisms have been predicted to enhance proteolytic cleavage of IL-6R from cell surfaces, thereby increasing levels of sIL-6R and subsequent signalling through IL-6- sIL-6R-gp130 complexes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
