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.

中文翻译：

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血管内皮特异性IL-4受体α-ABL1激酶信号转导轴调节IgE介导的过敏反应的严重性。

背景技术严重的IgE介导的，食物诱导的过敏反应的特征在于肺静脉血管扩张和液体外渗，其被认为导致威胁生命的过敏表型。尚未完全阐明涉及驱动液体外渗和严重过敏表型的潜在免疫和细胞过程。目的我们试图确定IL-4与血管内皮（VE）IL-4受体α链（IL-4Rα）信号传导在组胺-阿贝尔森鼠白血病病毒癌基因同源性1（ABL1）介导的VE功能障碍和体液中的相互作用和需求。 IgE介导的过敏反应在小鼠中的严重程度外渗。方法采用缺乏VEIL-4Rα的小鼠以及被动和主动口服抗原和IgE诱导的过敏反应模型来确定严重过敏反应中VEIL-4Rα和ABL1途径的需求。人类VE细胞系（EA.hy926细胞），药理学（伊马替尼）和遗传学（IL4RA和ABL1的短发夹RNA敲低）方法被用来定义VE屏障功能障碍中该途径的需求。结果组胺诱导的小鼠低血容量性休克的IL-4恶化取决于IL-4Rα的VE表达。IL-4和组胺诱导人VE细胞中的ABL1活化和VE屏障功能障碍是ABL1依赖性的。严重的IgE介导的血容量不足和休克的发展需要VE限制的ABL1表达。使用ABL激酶抑制剂伊马替尼治疗具有食物诱发过敏史的小鼠，可保护小鼠免受严重IgE介导的过敏反应。结论IL-4通过依赖于VEIL-4Rα/ ABL1的机制放大了IgE和组胺引起的VE功能障碍，液体外渗以及过敏反应的严重程度。这些研究暗示了VE隔室在过敏反应的严重性方面做出了重要贡献，并确定了治疗性干预IgE介导的反应的新途径。