Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis Valerie Hox, MD, PhD, Michael.

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Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis Valerie Hox, MD, PhD, Michael P. O'Connell, PhD, Jonathan J. Lyons, MD, Paul Sackstein, BS, Thomas Dimaggio, ADN, RN, Nina Jones, BSN, RN, Celeste Nelson, MS CRNP, Manfred Boehm, MD, Steven M. Holland, MD, Alexandra F. Freeman, MD, David J. Tweardy, MD, Ana Olivera, PhD, Dean D. Metcalfe, MD, Joshua D. Milner, MD Journal of Allergy and Clinical Immunology Volume 138, Issue 1, Pages 187-199 (July 2016) DOI: 10.1016/j.jaci.2015.11.024 Copyright © 2016 Terms and Conditions

Fig 1 Reduction in STAT3 levels confers resistance to anaphylaxis. A, Effect of C188-9 pretreatment (7 days) on body temperature changes in male C57Bl/6 mice during anaphylactic shock. Mice (n = 5-6 per group) were sensitized with 3 μg of DNP-specific IgE and challenged 24 hours later with 200 μg of DNP-HSA. B, Histamine and MCPT-1 released into the circulation (90 seconds) after challenge sensitized C188-9- or vehicle-treated mice to antigen (n = 6 per group). Results are presented as box plots with minimum/maximum range. C and D, Temperature changes during anaphylaxis induced by histamine (5 μmol) in C188-9- and vehicle-treated C57BL/6 (Fig 1, C) or AD-HIES (Fig 1, D) mice (n = 6 per group). E, Temperature changes during anaphylaxis induced by PAF (0.3 mg) in C188-9- and vehicle-treated mice. F, Survival curve of mice after PAF treatment (n = 6 per group in Fig 1, B, and n = 5 per group in Fig 1, C). *P < .05, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology 2016 138, 187-199DOI: (10.1016/j.jaci.2015.11.024) Copyright © 2016 Terms and Conditions

Fig 2 C188-9 decreases histamine- or PAF-induced vascular leakage. A and B, Hematocrit values at baseline and after passive systemic anaphylaxis induced by histamine (Fig 2, A) or PAF (Fig 2, B) in C188-9-treated (n = 5 per group) and vehicle-treated (n = 6 per group) mice. C and D, Evans Blue dye leakage in response to IgE/antigen c (n = 10 per group; Fig 2, C) or compound 48/80 (n = 5 per group; Fig 2, D) challenge in C188-9- and vehicle-treated mice. E and F, In vitro permeability assay of mouse lung endothelial cells exposed to histamine (1 μmol/L; Fig 2, E) or PAF (10 μg; Fig 2, F) after pretreatment with DMSO or C188-9 (1 μmol/L, n = 3 per group). His, Histamine; UT, untreated. Data are representative of 3 independent experiments and expressed as means ± SEMs. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2016 138, 187-199DOI: (10.1016/j.jaci.2015.11.024) Copyright © 2016 Terms and Conditions

Fig 3 C188-9 decreases vascular permeability through strengthening VE-cadherin junctions. A and B, In vitro permeability assay of HUVECs pretreated with DMSO or C188-9 (1 μmol/L) and subsequently exposed to histamine (100 μmol/L; Fig 3, A) or PAF (10 μg/mL; Fig 3, B). His, Histamine; UT, untreated. Data are representative of 3 independent experiments. C, Confocal microscopy of VE-cadherin (green), total β-catenin (red), and 4′-6-diamidino-2-phenylindole hydrochloride (DAPI; blue) in DMSO- and C188-9 (1 μmol/L)–pretreated HUVECs then subsequently exposed to histamine (100 μmol/L). D, Confocal microscopy of active (nonphosphorylated) β-catenin (green) and DAPI (blue) in DMSO- and C188-9 (1 μmol/L)–pretreated HUVECs then subsequently exposed to histamine (100 μmol/L). E, Western analysis of Stat3 and VE-cadherin signaling in DMSO- and C188-9–treated HUVECs. Data are expressed as means ± SEMs. *P < .05. Journal of Allergy and Clinical Immunology 2016 138, 187-199DOI: (10.1016/j.jaci.2015.11.024) Copyright © 2016 Terms and Conditions

Fig 4 HUVECs from patients with AD-HIES exhibit intrinsically decreased vascular permeability through increased VE-cadherin junctions. Patients with AD-HIES and healthy control subjects (n = 10 per group) underwent skin prick tests with increasing amounts of histamine. A and B, The area of the wheal (Fig 4, A) and flare (Fig 4, B) was recorded. C, Image of the bottom of a transwell chamber after exposure of WT HUVECs and HUVECs from patients with AD-HIES to the fluorescent reporter FITC-Dex (1 mg/well) for 30 minutes. D and E, In vitro permeability assay of WT HUVECs and HUVECs from patients with AD-HIES exposed to histamine (100 μmol/L; Fig 4, D) or PAF (10 μg/mL; Fig 4, E; n = 3 per group). His, Histamine; UT, untreated. Data are representative of 3 independent experiments. F, Immunofluorescent analysis of VE-cadherin (green), total β-catenin (red), and fluorescent isothiocyanate–dextran (DAPI; blue) in WT HUVECs and HUVECs from patients with AD-HIES after exposure to histamine (100 μmol/L). G, Western analysis of VE-cadherin in WT HUVECs and HUVECs from patients with AD-HIES after exposure to Wnt3A (200 ng/mL). Data are representative of 2 independent experiments. H, In vitro permeability assay of WT HUVECs (left panel, n = 3 per group) and HUVECs from patients with AD-HIES (right panel, n = 3 per group) pretreated with Wnt3A (200 ng/mL) and subsequently exposed to histamine. Data are representative of 3 independent experiments. Data are means ± SEMs. *P < .05 and **P <.01. Journal of Allergy and Clinical Immunology 2016 138, 187-199DOI: (10.1016/j.jaci.2015.11.024) Copyright © 2016 Terms and Conditions

Fig 5 HUVEC permeability is regulated by STAT3-induced mir17-92 and can be restored in cells from patients with AD-HIES through the canonical Wnt signaling pathway. A, Western blot analysis of phosphorylated Src, total Src, and phosphorylated PTEN in DMSO- and C188-9-treated HUVECs after exposure to histamine (100 μmol/L). B and C, Western blot analysis of phosphorylated VE-cadherin, total VE-cadherin, active (nonphosphorylated) β-catenin, total β-catenin, phosphorylated Src, total Src, phosphorylated PTEN, total PTEN, and phosphorylated STAT3 in WT HUVECs and HUVECs from patients with AD-HIES after exposure to histamine (100 μmol/L). Data are means ± SEMs. *P < .05. D, Real-time PCR analysis of mir17-95 RNA expression in IL-11 (100 ng/mL)–treated WT HUVECs and HUVECs from patients with AD-HIES. Data are representative of 3 independent experiments. E, Western blot analysis of SIAH1 and E2F1 expression in WT cells and cells from patients with AD-HIES. Data are representative of 2 independent experiments. F, Analysis of cytoplasmic verses nuclear active β-catenin in WT HUVECs and HUVECs from patients with AD-HIES. Journal of Allergy and Clinical Immunology 2016 138, 187-199DOI: (10.1016/j.jaci.2015.11.024) Copyright © 2016 Terms and Conditions

Fig 6 PTEN inhibition restores STAT3-inhibited or mutated HUVECs permeability. A, PTEN expression in WT HUVECs and HUVECs from patients with AD-HIES after transfection with a mir19 mimic. B, PTEN expression in STAT3-inhibited WT HUVECs over 7 days. C, Expression of phosphorylated Src in PTEN inhibitor–pretreated HUVECs (1 hour) that were subsequently exposed to histamine (100 μmol/L). D and E, In vitro permeability assay of DMSO- or C188-9-treated HUVECs (Fig 6, D) or WT HUVECs and HUVECs from patients with AD-HIES treated with a PTEN inhibitor (1 hour) and subsequently exposed to histamine (100 μmol/L; Fig 6, E). Data are means ± SEMs. *P < .05. F, Model of STAT3 regulation of vascular permeability in WT HUVECs and HUVECs from patients with AD-HIES. In WT cells histamine treatment leads to Src phosphorylation, resulting in dissociation of β-catenin and internalization and degradation of VE-cadherin. Under conditions of normal STAT3 signaling, STAT3 induces expression of the mir17-92 microRNA cluster that suppresses PTEN, E2F1, and SIAH1 levels. This allows for normal regulation of Src signaling and normal distribution of β-catenin cellular dynamics and thus directly regulates the amount of VE-cadherin and β-catenin. In STAT3-mutated cells histamine treatment leads to no Src phosphorylation because of decreased expression of mir17-92 resulting in increased PTEN. This prevents the internalization and degradation of VE-cadherin, ultimately increasing its expression. Mir17-92 deficiency also allows for increased E2F1 and SIAH1 expression. This will degrade any phosphorylated β-catenin in the cytoplasm and inhibits nuclear translocation of nonphosphorylated cytoplasmic β-catenin, which provides more nonphosphorylated β-catenin to form adherens junctions, leading to decreased vascular permeability. Journal of Allergy and Clinical Immunology 2016 138, 187-199DOI: (10.1016/j.jaci.2015.11.024) Copyright © 2016 Terms and Conditions