Soluble ADAM33 augments the pulmonary innate immune response promoting susceptibility to allergic airway inflammation

A disintegrin and metalloproteinase 33 (ADAM33) is an asthma susceptibility gene. A soluble, catalytically active form (sADAM33) has been identified in bronchoalveolar lavage fluid, levels of which correlate with disease severity. To model the role of sADAM33 in asthma, a transgenic mouse, expressing human sADAM33 was generated. sADAM33 mice were found to be more susceptible than controls to allergic airways disease. This led to the hypothesis that induction of sADAM33 expression changes the underlying immune microenvironment in the airway, promoting susceptiblity to allergic airways disease. To study this, RNA samples from whole lungs of sADAM33 mice and control mice were sequenced for differential expression analysis. Gene ontology identified predominantly immune-related biological processes associated with sADAM33 expression. Validation across a wider cohort of samples using RTqPCR confirmed the up-regulation of lymphocyte effector cell markers (Nkp46, Gzmb), as well as negative regulators of effector responses (Ido1, Pd-l1). Protein levels of GZMB measured by ELISA were significantly increased in sADAM33 mice. Analysis of lymphocyte populations by flow cytometry identified an increased population of CD3-, NKp46+, KLRG1+ positive lymphocytes, which may represent an altered phenotype of innate lymphocyte populations in the airway. The biology of innate lymphocytes is complex, but there is increasing support for their involvement in allergic disease. The altered phenotype of this cell population within the sADAM33 mice may play an important role in their increased susceptibility to allergic airways disease and warrants further investigation.