ADAMTS4 promotes chronic airway inflammation and hyperresponsiveness in HDM-based mouse model of asthma: A potential therapeutic target for asthma traits

Abstract Asthma is a chronic airway inflammation characterized by combination of immune responses and structural remodeling that involves both large and small airways. The global prevalence of asthma is on the rise with a sizable portion of asthmatics not responding to existing medication, thus posing a substantial health and economic burden. Matrix proteases including A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) contribute to lung damage and repair responses. Our lab has recently reported a critical role for ADAMTS4 in the immunopathology of IAV infection-induced acute lung inflammation through exuberant activity of lung fibroblasts and remodeling of the extracellular matrix. Given the divergent nature of immune responses in chronic airway inflammation compared to infection, we sought to investigate the sustaining role of ADAMTS4 upon persistent exposure to aeroallergen. Using HDM-based asthma model, ADAMTS4 knockout mice exhibited a robust reduction in lung eosinophils, mucus production, and airway resistance compared to their wildtype counterparts. This was associated with a marked decrease in IL-4, IL-5, and IL-13 cytokine production and IgE secretion. Interestingly, ADAMTS4 gene deletion differentially blocked the myeloid cell recruitment to the lungs without affecting their development. Such effects were also associated with significant reduction in alveolar macrophages and peribranchial inflammation. These results suggest that the modulating immune responses by ADAMTS-4 is sustainable beyond the acute phase of inflammation and may be extensively contributing to the immunopathology of chronic airway inflammation, thus harboring a therapeutic potential for the treatment of asthma traits.