Targeting ADAM17 to dampen dendritic cell-mediated type 2 immune responses and airway inflammation associated with allergic asthma.

Abstract

The zinc containing matrix metalloproteinase enzyme regulates a diverse array of biological processes in health and disease, including ADAM17 (a disintegrin and metalloproteinase domain 17) enzyme. Due to its large substrate profile, ADAM17 is known to regulate diverse pathways of inflammation and adaptive immunity. However, the role of ADAM17 in modulating the pathogenesis of type 2 allergic asthma is largely unknown. To determine the in vivo contribution of ADAM17 in house dust mite (HDM)-induced airway inflammation and adaptive immune response, we assessed the deletion of ADAM17 in mice conventional dendritic cells (ΔDC) and employed a complementary chemical biology approach using small-molecule novel ADAM17 inhibitor (2155-17). DC-specific ADAM17 ablation (ΔDC) suppressed type 2/ eosinophilic polarized HDM allergic responses and is protected from developing AHR. DC isolated from ΔDC mice showed a reduced state of metabolic activity, immune priming function and suppressed allergen-specific type 2 cell polarizations. Intranasal administration of 2155-17 protected WT mice against type2/ eosinophilic polarized HDM allergic responses. These concurrent results from two independent approaches identify a novel role for ADAM17 as an upstream site in airway inflammation. Furthermore, targeting ADAM17 with a selective small-molecule inhibitor might be harnessed as a potential drug target for type 2-high allergic asthma.