The vascular endothelial specific IL-4 receptor alpha–ABL1 kinase signaling axis regulates the severity of IgE-mediated anaphylactic reactions

Abstract

Background Severe 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. Objective To 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. Methods Mice 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. Results IL-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. Conclusion IL-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 pathway for therapeutic intervention of IgE-mediated reactions.

Genetic inhibition of NFATC2 attenuates asparaginase hypersensitivity in mice

“…However, it is also feasible that other mechanisms contribute to the difference in anaphylaxis between immunized WT and KO mice, such as an attenuation in the severity of anaphylaxis as a result of decreased IL-4 and/or IL-13 levels and their synergistic action with vasoactive mediators to increase vascular permeability. 32,33 Consistent with this possibility, ASNase-immunized KO mice developed less Figure 5A), whereas no difference in the severity of shock was detected between histamine-injected naïve WT and KO mice. Likewise, immunized NFATC2 KO mice developed less severe anaphylaxis relative to WT controls when directly challenged with ASNase ICs ( Figure 5B; supplemental Figure 5A-B), although differences in the severity by genotype were dose dependent, indicating that both the levels of vasoactive mediators released upon degranulation and the differential cytokine levels are required to demonstrate exacerbated anaphylaxis in WT mice.…”

Mechanisms of Dupilumab

“…In addition to that, IL‐4R has an important role as well in the amplification of IgE‐ and histamine‐induced vascular endothelium (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/IL‐4‐mediated reactions.…”

IL-13–induced intestinal secretory epithelial cell antigen passages are required for IgE-mediated food-induced anaphylaxis

“…Rectal temperature and hemoconcentration were measured, as previously described. 27 FIG 3. IL-13 is sufficient to drive SAP formation, and secretory cells are required for SAP formation.…”

“…WT BALB/c mice received rmIL-4 (65 ng/200 mL administered intravenously), and 24 hours later, we examined MHC class II expression on splenic B220 1 B cells and evidence of SI SAPs to test whether IL-4 is sufficient to drive SAPs, as previously described. 27 BALB/c mice that had demonstrated evidence of anaphylaxis after the fifth challenge were stratified into either isotype control or anti-IL-13Ra1 mAb treatment groups and received either isotype control mouse IgG 1 (4.5-5.5 g; MOPC-21, mouse IgG 1 ; BioXCell, Lebanon, NH) or anti-mouse IL-13Ra1 antibody (clone MS8, mouse IgG1-Kappa; 4.5-5.5 g) on days 23, 25, and 27 of the experimental regimen to determine the requirement of IL-13-driven SAPs in the induction of a food-induced anaphylactic reaction. On day 28, mice received the seventh oral OVA challenge, and evidence of a foodinduced anaphylactic reaction and SI SAPs was examined.…”