Loss of IL‐4Rα–mediated PI3K signaling accelerates the progression of IgE/mast cell–mediated reactions. Issue 4 (17th September 2015)

• Record Type: Journal Article
• Authors: Sledd, Jane; Wu, David; Ahrens, Richard; Lee, Jeebong; Waggoner, Lisa; Tsai, Ying Ting; Wang, Yui‐Hsi; Hogan, Simon P.
• Is Part Of: Immunity, inflammation and disease. Volume 3:Issue 4(2015)
• Page Start: 420
• Page End: 430
• Publication Date: 2015-09-17
• Subjects: food‐induced anaphylaxis -- IgE and mast cells -- interleukin 4 (IL‐4) receptor (IL‐4R) chain; Immunology -- Periodicals; Immunity -- Periodicals; Inflammation -- Periodicals; 616.079
• DOI: 10.1002/iid3.80
• Languages: English
• ISSNs: 2050-4527

Abstract

Abstract: Clinical and experimental evidence indicate that polymorphisms within the interleukin 4 (IL‐4) receptor (IL‐4R) chain are sufficient for altered strength of IL‐4/IL‐13 signaling, leading to an exaggerated allergic inflammatory response and increase susceptibility to allergic phenotypes. In the present study, we show that ablation of IL‐4Rα–induced phosphatidylinositol 3‐kinase (PI3K) activating signal by germline point mutation within the IL‐4Rα motif (Y500F) did not alter susceptibility to IgE‐mediated, food‐induced experimental anaphylaxis. Moreover, diarrhea occurrence, antigen‐specific IgE and intestinal mastocytosis were comparable between WT and IL‐4Rα Y500F mice. However, mice unable to stimulate IL‐4Rα–mediated PI3K signaling had accelerated disease progression. Notably, the accelerated anaphylactic response was associated with more rapid histamine‐induced hypovolemia. Mechanistic in vitro and in vivo analyses revealed that endothelial IL‐4Rα PI3K signaling negatively regulates the histamine‐induced endothelial leak response. These results define an unanticipated role for IL‐4Rα–mediated PI3K signaling in negative regulation of IgE‐mediated anaphylactic reactions. Abstract : Employing a mouse model of food‐induced IgE‐reactions, we show that genetic ablation of IL‐4Ra–mediated PI3K signaling leads to accelerated onset and progression of food‐induced anaphylaxis. We report that the accelerated disease progression is not related to altered IgE‐mast cell function, but rather due to altered histamine‐induced vascular endothelial leak and rapid shock response.