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

Area of Science:

• Immunology
• Allergy Research
• Matrix Metalloproteinases

Background:

• ADAM17 (a disintegrin and metalloproteinase domain 17) is a zinc-containing enzyme regulating biological processes.
• ADAM17 influences inflammation and adaptive immunity due to its broad substrate profile.
• The specific role of ADAM17 in type 2 allergic asthma pathogenesis remains largely unexplored.

Purpose of the Study:

• To investigate the in vivo role of ADAM17 in house dust mite (HDM)-induced airway inflammation and adaptive immune responses.
• To assess the impact of dendritic cell-specific ADAM17 deletion (ΔDC) on allergic asthma.
• To evaluate the efficacy of a novel small-molecule ADAM17 inhibitor (2155-17) in a mouse model.

Main Methods:

• Generation of dendritic cell-specific ADAM17-deficient mice (ΔDC).
• Induction of allergic airway inflammation using house dust mite (HDM) exposure.
• Administration of a novel small-molecule ADAM17 inhibitor (2155-17).
• Assessment of airway hyperresponsiveness (AHR), eosinophilic polarization, and immune cell function.

Main Results:

• Dendritic cell-specific ADAM17 ablation (ΔDC) significantly suppressed type 2/eosinophilic allergic responses and protected against AHR.
• ADAM17-deficient dendritic cells exhibited reduced metabolic activity, impaired immune priming, and suppressed allergen-specific type 2 cell polarization.
• Intranasal administration of the ADAM17 inhibitor 2155-17 protected wild-type mice from type 2/eosinophilic HDM-induced allergic responses.

Conclusions:

• ADAM17 plays a critical upstream role in mediating airway inflammation in type 2 allergic asthma.
• Targeting ADAM17 with selective small-molecule inhibitors presents a potential therapeutic strategy for type 2-high allergic asthma.