ADAM 10 and Notch1 on murine dendritic cells control the development of type 2 immunity and IgE production

• Published in: Allergy (Copenhagen) Vol. 73; no. 1; pp. 125 - 136
• Main Authors: Damle, S. R., Martin, R. K., Cockburn, C. L., Lownik, J. C., Carlyon, J. A., Smith, A. D., Conrad, D. H.
• Format: Journal Article
• Language: English
• Published: 01.01.2018
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/all.13261

Abstract Background Allergy and allergic asthma are significant health burdens in developed countries and are increasing in prevalence. Dendritic cells ( DC s) initiate immune responses to common aeroallergens, and ADAM 10 has been demonstrated to be important for the development of adaptive responses. This study's objective was to understand the role of ADAM 10 on DC s in the development of allergic and anaphylactic responses. Methods In this study, we used mouse models of allergic airway inflammation (house dust mice and Alternaria alternata ) and OVA ‐induced models of active anaphylaxis to determine the DC ‐specific function of ADAM 10 and Notch signaling. To examine T H 1 and T H 17 immunity infection with Anaplasma phagocytophilum and Citrobacter rodentium respectively, were used. Results Mice, which have ADAM 10 deleted from DC s, have dramatic reductions in IgE production and do not develop significant T H 2 immune responses. Further, ADAM 10 DC −/− mice are resistant to IgE‐mediated anaphylaxis. This response is selective for T H 2 immunity as T H 1 and T H 17 immunity is largely unaffected. Notch1, a known ADAM 10 substrate, when knocked out of DC s (Notch1 DC −/− ) demonstrated a similar reduction in anaphylaxis and IgE. Without ADAM 10 and Notch1 signaling, DC s were unable to make cytokines that stimulate T H 2 cells and cytokines. Anaphylaxis and allergic lung inflammation were restored in ADAM 10 DC −/− with the overexpression of the Notch1‐intracellular domain, confirming the role of Notch signaling. Conclusions Targeting ADAM 10 and Notch1 on DC s represent a novel strategy for modulating T H 2 immune responses and IgE production.