Loss of A Disintegrin And Metalloproteinase 10 (ADAM10) in dendritic cells dampens type 2 immune responses.

Abstract

Abstract Allergy and allergic asthma are significant health burdens in developed countries and are increasing in prevalence. Current therapeutic strategies focus on management of disease symptoms, but are unable to control disease initiation. Previous reports from our lab demonstrated a reduction in type 2 (Th2) immune responses with ADAM10 inhibition. Thus, we sought to understand the role of ADAM10 in immune cells involved in Th2 responses, specifically dendritic cells (DCs). We generated mice which have ADAM10 deleted from DCs using mice that express Cre recombinase driven by the CD11c promoter (A10DCKO mice). We used a house dust mite (HDM) extract model of allergic airway inflammation and demonstrated a drastic reduction in airway resistance in the A10DCKOs as well as a reduction in eosinophils. We also found a reduction in Th2 cytokine expression, HDM specific IgG1 antibody, and lung inflammation in the A10DCKOs. After administration of inhaled antigen we found a significant reduction in antigen specific T cell proliferation in the spleen of the A10DCKOs, but no difference in the mediastinal lymph nodes. To understand the mechanism and given the importance of ADAM10 in Notch signaling, we compared the phenotype of the A10DCKOs to published reports of Notch2 DC-specific KOs. The A10DCKOs had a similar reduction in total conventional, CD172+, and CD172+ ESAM+ DCs in the spleen. However, we saw no decreases in other DC populations in the spleen and mesenteric lymph node demonstrated in the Notch2 KO, indicating a role for ADAM10 separate from Notch2 signaling. Overall, these results point to a mechanism of action of an ADAM10 inhibitor and a novel strategy for modulating Th2 immune responses.