CD131 antagonism blocks inflammation, emphysema and fibrosis in an asthma-COPD overlap mouse model originating in early life.

BACKGROUND AND

OBJECTIVE

Asthma-COPD overlap (ACO) is characterized by patients exhibiting features of both asthma and COPD. Currently, there is no specific treatment for ACO. This study aimed to investigate the therapeutic potential of targeting CD131, a shared receptor subunit for IL-3, IL-5 and GM-CSF, in ACO development and in preventing acute viral exacerbations.

METHODS

A two-hit mouse model of ACO was established by house dust mite (HDM) allergen sensitization to model asthma, and elastase treatment to model emphysema. In a separate model, human rhinovirus 1b (RV1b) was used to induce an acute asthma exacerbation. A neutralizing antibody against CD131 was used to block CD131 in vivo signalling.

RESULTS

Mice exposed to HDM and elastase developed cardinal features for asthma and COPD, including airway hyperreactivity (AHR) and emphysema. A mixed granulocytic inflammatory profile was identified in the lungs, including expansion of monocyte-derived macrophages, neutrophils and eosinophils. RT-qPCR analysis detected heightened gene expression of Mmp12, Il5 and Il13. Transcriptomic analysis further revealed pathway enrichment for type 2 inflammation and macrophage activation. Blockade of CD131 effectively reduced the lung inflammation and prevented the development of AHR, airway fibrosis and emphysema. Interestingly, pathway enrichment for Th1 response and interferon production detected in the model was not affected by the treatment. Consistently, CD131 antagonism prevented RV1b-induced asthma exacerbation without compromising RV1b clearance.

CONCLUSION

CD131 signalling coordinates multiple pathological pathways that drive airway inflammation and lung remodelling in ACO. Hence, CD131 antagonism represents a novel approach to combating the immunopathology in the complex ACO setting.