The vascular endothelial specific IL-4 receptor alpha–ABL1 kinase signaling axis regulates the severity of IgE-mediated anaphylactic reactions - 05/10/18
Abstract |
Background |
Severe IgE-mediated, food-induced anaphylactic reactions are characterized by pulmonary venous vasodilatation and fluid extravasation, which are thought to lead to the life-threatening anaphylactic phenotype. The underlying immunologic and cellular processes involved in driving fluid extravasation and the severe anaphylactic phenotype are not fully elucidated.
Objective |
We sought to define the interaction and requirement of IL-4 and vascular endothelial (VE) IL-4 receptor α chain (IL-4Rα) signaling in histamine-abelson murine leukemia viral oncogene homology 1 (ABL1)–mediated VE dysfunction and fluid extravasation in the severity of IgE-mediated anaphylactic reactions in mice.
Methods |
Mice deficient in VE IL-4Rα and models of passive and active oral antigen– and IgE-induced anaphylaxis were used to define the requirements of the VE IL-4Rα and ABL1 pathway in severe anaphylactic reactions. The human VE cell line (EA.hy926 cells) and pharmacologic (imatinib) and genetic (short hairpin RNA knockdown of IL4RA and ABL1) approaches were used to define the requirement of this pathway in VE barrier dysfunction.
Results |
IL-4 exacerbation of histamine-induced hypovolemic shock in mice was dependent on VE expression of 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 severe IgE-mediated anaphylaxis.
Conclusion |
IL-4 amplifies IgE- and histamine-induced VE dysfunction, fluid extravasation, and the severity of anaphylaxis through 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 pathway for therapeutic intervention of IgE-mediated reactions.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : IL-4 receptor α chain, hypovolemic shock, IgE and mast cells, food-induced anaphylaxis, histamine, vascular endothelial barrier dysfunction, ABL1 kinase
Abbreviations used : ABL1, AJ, CCHMC, HRP, iIL-9Tg, IL-4C, IL-4Rα, LB, MC, mMCPT-1, OVA, shRNA, TER, TJ, TKI, TNP, VE, WT
Plan
| Supported by National Institutes of Health grants R01 AI073553, R01 AI 112626, R01 DK090119 (to S.P.H.), P30DK078392, and U19A1070235 and a Food Allergy Research Education Award (to S.P.H.). |
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| Disclosure of potential conflict of interest: A. Yamani receives funding from grants from the National Institutes of Health (NIH) and Food Allergy Research & Education (FARE). D. Wu receives funding from grants from the NIH and FARE. L. Waggoner receives funding from grants from the NIH and FARE. T. Noah receives funding from rants from the NIH and FARE. A. J. Koleske receives funding from grants from the NIH and FARE. F. Finkelman receives fees or funding for consultancy from Vedanta Bioscience, is employed by the University of Cincinnati and Fress Therapeutics, and receives grants from NIH, FARE, the University of Cincinnati, Cincinnati Children's Hospital. S. P. Hogan receives funding from grants from the NIH and FARE. |
Vol 142 - N° 4
P. 1159 - octobre 2018 Retour au numéro
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