Vascular endothelial specific IL-4Rα–ABL1 kinase signaling axis regulates severity of IgE-mediated anaphylactic reactions

Publication date: Available online 17 November 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Amnah Yamani, David Wu, Lisa Waggoner, Taeko Noah, Anthony J. Koleske, Fred Finkelman, Simon P. Hogan
BackgroundSevere IgE-mediated, food-induced anaphylactic reactions are characterized by pulmonary venous vasodilatation and fluid extravasation, which is thought to lead to the life-threatening anaphylactic phenotype. The underlying immunological and cellular processes involved in driving fluid extravasation and the severe anaphylactic phenotype are not fully elucidated.ObjectiveTo define the interaction and requirement of IL-4 and vascular endothelial (VE) IL-4Rα chain signaling in histamine-ABL1–mediated VE dysfunction and fluid extravasation in the severity of IgE-mediated anaphylactic reactions in mice.MethodsMice deficient in VE IL-4Rα and models of passive and active oral antigen– and IgE-induced anaphylaxis were employed to define the requirements of VE IL-4Rα and ABL1 pathway in severe anaphylactic reactions. Human VE cell line (EA.hy926 cells) and pharmacologic (imatinib) and genetic approaches (shRNA knockdown of IL4RA and ABL1) were used to define the requirement of this pathway in VE barrier dysfunction.ResultsIL-4 exacerbation of histamine-induced hypovolemic shock in mice was dependent on VE expression of the IL-4Rα. IL-4 and histamine induced ABL1 activation in human VE cells and VE barrier dysfunction was ABL1 dependent. Development of severe IgE-mediated hypovolemia and shock required VE-restricted ABL1 expression. Treatment of mice with a history of food-induced anaphylaxis with the ABL kinase inhibitor imatinib protected the mice from developing severe IgE-mediated anaphylaxis.ConclusionIL-4 amplifies IgE- and histamine-induced VE dysfunction, fluid extravasation, and severity of anaphylaxis via a VE IL-4Rα-ABL1–dependent mechanism. These studies implicate an important contribution by the VE compartment in the severity of anaphylaxis and identify a new

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Capsule Summary: IL-4-Histamine induced vascular endothelial cell ABL1 kinase signaling controls severity of IgE-mediated anaphylactic reactions.


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