D1.174 - Framing ADAM17 alterations across bronchial, sputum and nasal sites in asthma and controls

A disintegrin and metalloproteinase 17 (ADAM17) regulates inflammation and epithelial repair through shedding of many asthma-related cytokines and receptors, yet its role across the airways remains unclear. This study investigated ADAM17 expression and its soluble substrates in the upper and lower airways with matched blood samples across three cohorts of individuals with asthma and healthy controls. 

The lower airway cohort included bronchoalveolar lavage supernatant and bronchial biopsies (asthma: n=11/controls: n=7) alongside blood supernatant (n=28/25). The mixed airway cohort included sputum supernatant (n=13/6) and blood cells with blood supernatant (n=12/9).  The upper airway cohort included nasal lavage supernatant (n=12/12) and blood supernatant (n=11/11). Cell-based samples were analysed for ADAM17 and hyperactive phosphorylated (p)-ADAM17 expression by immunofluorescence and flow cytometry. Supernatants were quantified for ADAM17 (ELISA) and up to 29 of its substrates (Luminex). 

Among the non-granulocytic circulating cells we found that the majority of ADAM17 was expressed on the lymphocytes (T-, B- and NKT-cells), although substrate levels were not consistent across the three cohorts. In the airways, we found that asthma bronchial biopsies had higher proportions of ADAM17+pADAM17- epithelial cells (p = 0.034). Asthma NAL also had ADAM17+ epithelial cells while asthma sputum contained pADAM17+ cells, primarily macrophages with some neutrophils. Interestingly, we detected extracellular aggregates of ADAM17 and/or pADAM17 across all airway compartments. Of the soluble substrates cleaved by ADAM17, asthma sputum supernatant had the greatest number of difference with significantly higher levels of TGF-α (p = 0.025), TNFRII (p = 0.039) and IL-6R (p = 0.042) – previously reported in asthma sputum – but also, higher levels of APP (p = 0.001) HB-EGF (p = 0.020) and IL-1RII (p = 0.025) not yet reported in asthma sputum. 

These findings indicate compartment-specific dysregulation of ADAM17 activity in asthma, most prominently within the lower airways. This study also highlights ADAM17 as a central enzymatic node linking epithelial activation and inflammatory signalling within asthma airways.