Transient targeting of phosphoinositide 3-kinase acts as a roadblock in mast cells' route to allergy Emilie Collmann, PhD, Thomas Bohnacker, PhD, Romina.

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Presentation transcript:

Transient targeting of phosphoinositide 3-kinase acts as a roadblock in mast cells' route to allergy Emilie Collmann, PhD, Thomas Bohnacker, PhD, Romina Marone, PhD, Janet Dawson, PhD, Markus Rehberg, PhD, Rowan Stringer, PhD, Fritz Krombach, PhD, Christoph Burkhart, PhD, Emilio Hirsch, PhD, Gregory J. Hollingworth, PhD, Matthew Thomas, PhD, Matthias P. Wymann, PhD Journal of Allergy and Clinical Immunology Volume 132, Issue 4, Pages 959-968 (October 2013) DOI: 10.1016/j.jaci.2013.03.008 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IgE-induced mast cell recruitment is p110γ dependent in vivo and in vitro. A and B, Mast cell numbers per square millimeter were quantified in ear and back skin biopsy specimens from wild-type (wt), p110γKO, p110γKR, and p110δDA mice before (Fig 1, A) and after (Fig 1, B) intradermal IgE (SPE-7; solid lines) or PBS (dashed lines) challenge for 24 or 48 hours (3 mice per group, 6 tissue sections per mouse, mean ± SEM). *P < .001. Fig 1, A, Comparison versus wild-type mice; Fig 1, B, IgE (SPE-7) vs PBS. C, Representative pictures of back skin biopsy specimens after Toluidine-Blue-O staining. D, Quantification of BMMC migration toward 20 ng/mL SCF, 1 μmol/L adenosine, 10 nmol/L IB-MECA, 1 μg/mL SPE-7 IgE, or 100 ng/mL SPE-7 IgE overnight plus antigen (DNP-HSA, 10 ng/mL) through fibronectin-coated Transwells for 6 hours at 37°C (n > 3, mean ± SEM). &P < .05 and *P < .001. Journal of Allergy and Clinical Immunology 2013 132, 959-968DOI: (10.1016/j.jaci.2013.03.008) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Contribution of p110γ and p110δ to FcεRI-induced BMMC responses. A and B, Phosphorylation of PKB in SPE-7 IgE–sensitized wild-type (wt), p110γKO, and p110δDA BMMCs after stimulation with indicated amounts of antigen (DNP-HSA for 2 minutes; Fig 2, A) or for indicated times with 5 ng/mL DNP-HSA (Fig 2, B; n = 3, mean ± SEM). $P < .01. C and D, β-Hexosaminidase release from IgE (SPE-7)–sensitized wild-type, p110γKO, and p110δDA BMMCs (Fig 2, C) and from inhibitor-treated wild-type BMMCs after antigen exposure (DNP-HSA; Fig 2, D; n > 3, mean ± SEM). $P < .01 and *P < .001. E and F, TNF-α (Fig 2, E) and IL-6 (Fig 2, F) release to supernatants from gene-targeted or chemically inhibited BMMCs after stimulation with IgE/antigen (SPE-7/DNP-HSA) with or without adenosine (n = 3, mean ± SEM). &P < .05 and *P < .001. Journal of Allergy and Clinical Immunology 2013 132, 959-968DOI: (10.1016/j.jaci.2013.03.008) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 VCAM-1 expression on endothelium is mediated by TNF-α, and VCAM-1 expression is largely dependent on the presence of p110γ in BMMCs. A, VCAM-1 expression on HUVECs exposed to supernatants from activated wild-type (wt), p110γKO, and p110δDA BMMCs was determined by means of FACS after 16 hours (n > 3, mean ± SEM). &P < .05 and *P < .001. B, HUVECs were exposed to wild-type BMMC supernatants previously incubated with anti–TNF-α antibody, anti–IL-1β antibody, or Enbrel for 1 hour at 37°C. VCAM-1 surface expression was analyzed as in Fig 3, A (n = 3, mean ± SEM). *P < .001. Journal of Allergy and Clinical Immunology 2013 132, 959-968DOI: (10.1016/j.jaci.2013.03.008) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Modulation of vascular permeability by targeting p110γ and p110δ. Wild-type (wt), p110γKO, and p110δDA mice were injected intradermally with SPE-7 IgE (solid bars) or PBS (dashed bars). After 48 hours, antigen (DNP-HSA) in 0.5% Evans Blue/PBS was injected intravenously. A, The indicated SPE-7 IgE concentrations and 25 μg of DNP-HSA were applied. B, IgE (10 ng of SPE-7) or PBS was combined with indicated DNP-HSA doses. Vascular permeability was visualized by using Evans Blue extravasation and quantified at 620 nm (6 mice per condition, mean ± SEM). &P < .05 and $P < .01. C, Protocol of repetitive (1 or 3 mg/kg) and acute (10 or 30 mg/kg) isoform-specific PI3K inhibitor (red, NVS-PI3-4; green, IC87114) or Enbrel (10 mg/kg; yellow) dosage. Biopsy specimens were taken or mice were challenged with DNP-HSA 48 hours after IgE (SPE-7) injection (intradermal). D, Mast cells per square millimeter at injection sites were analyzed in SPE-7 IgE– or PBS-injected wild-type mice with repetitive or single inhibitor treatments. Toluidine-Blue-O–stained cells were counted (6 sections per mouse of 3 mice per group were analyzed, mean ± SEM). &P < .05 and *P < .001. E, IgE (10 ng of SPE-7)– or PBS-injected mice were dosed with PI3K inhibitors (left) or Enbrel (right), as mentioned in Fig 4, C, and injected intravenously with 25 μg of DNP-HSA in 0.5% Evans Blue 48 hours later. The PCA response was measured as in Fig 4, A (6 mice per group, mean ± SEM). $P < .01 and *P < .001. F, Mice were treated with NVS-PI3-4 or IC87114, as described in Fig 4, C, and tissues were sampled to analyze inhibitor concentrations in blood and skin (see the Methods section for sample collection procedures) 1 hour after the last administration of inhibitor (n = 4 mice each). G, Cells were exposed to 5 μmol/L NVS-PI3-4 or 200 nm of wortmannin for 30 minutes, followed by removal of inhibitor. The indicated time reflects the duration after inhibitor removal until stimulation with 2 μmol/L adenosine (2 minutes). BMMCs were starved (IL-3 depleted) 3 hours before stimulation. Normalized PKB/Akt phosphorylation on Ser473 is shown as means ± SEMs (n = 3-4). Journal of Allergy and Clinical Immunology 2013 132, 959-968DOI: (10.1016/j.jaci.2013.03.008) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 In vivo mast cell adhesion and recruitment. A, Four hours after stimulation with TNF-α, rolling (left panel) and firmly adherent (right panel) mast cells were quantified in wild-type (wt) cremaster muscle by using in vivo fluorescence microscopy. The average number of cells per minute per 10-mm2 surface area is depicted (5 mice per condition, mean ± SEM). &P < .05 compared with wild-type mice. B, Microscopic images. One CellTracker Green–labeled wild-type mast cell is shown as it rolls on activated endothelium in a postcapillary venule from right to left. The 4 assembled frames were taken at the times indicated at the top (see also Video E1). C, In vitro adhesion of carboxyfluorescein succinimidyl ester–labeled BMMCs (wild-type, p110γKO, and p110δDA) to HUVECs on incubation with 20 ng/mL SCF, 1 μmol/L adenosine, 10 nmol/L IB-MECA, 10 nmol/L C5a, 10 nmol/L SDF-1α, or 10 nmol/L RANTES (n > 3, mean ± SEM). *P < .001. D, Integrin expression on BMMCs was determined by using FACS with anti-α4, anti-α5, and anti-β1 biotinylated antibodies combined with phycoerythrin-streptavidin. E, Effect of anti-IgE, anti–IL-1β, isotype control, or Enbrel pretreatment (12 hours, intraperitoneal) on SPE-7 IgE–induced (24 hours, intradermal) mast cell recruitment in wild-type mice. Toluidine-Blue-O–positive cells were counted with a light microscope (6 sections per mouse of 3 mice per group were analyzed, mean ± SEM). *P < .001 compared with wild-type isotype-treated mice. Journal of Allergy and Clinical Immunology 2013 132, 959-968DOI: (10.1016/j.jaci.2013.03.008) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Requirement of p110γ activity in the sequential steps of allergy. The priming phase preceding an acute allergic response requires local IgE, which docks to FcεRI on tissue-resident mast cells. Thereby VLA-5 is activated in a PI3Kγ-dependent manner, which increases adhesion of mast cells to extracellular matrix proteins, such as fibronectin, which regulates mast cell responsiveness. Responsive tissue mast cells release TNF-α, thereby activating endothelial cells, which provide docking sites (VCAM-1) for vascular mast cell precursors. Mast cell precursors activate α4β1 (VLA-4) on paracrine GPCR signaling through PI3Kγ close to the inflamed endothelium, which allows docking to VCAM-1 and eventually extravasation. Increased numbers of mast cells are thus present in challenged tissue after the PI3Kγ-dependent recruitment phase. A subsequent challenge with antigen combined with the p110γ-dependent autocrine/paracrine signaling then leads to allergic symptoms, such as increased vascular permeability. HSC, Hematopoietic stem cell; MCP, mast cell precursor. Journal of Allergy and Clinical Immunology 2013 132, 959-968DOI: (10.1016/j.jaci.2013.03.008) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions