CD13/aminopeptidase N is a negative regulator of mast cell activation

Julia S.  Zotz; Florian  Wölbing; Caroline Lassnig; Marlies  Kauffmann; Uwe Schulte; Andreas Friedrich Kolb; Bruce Whitelaw; Mathias Müller; Tilo Biedermann; Michael Huber

doi:10.1096/fj.201600278

CD13/aminopeptidase N is a negative regulator of mast cell activation

Julia S. Zotz, Florian Wölbing, Caroline Lassnig, Marlies Kauffmann, Uwe Schulte, Andreas Friedrich Kolb, Bruce Whitelaw, Mathias Müller, Tilo Biedermann, Michael Huber

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

Antigen-induced mast cell (MC) activation via cross-linking of IgE-bound high-affinity receptors for IgE (FcεRI) underlies type I allergy and anaphylactic shock. Comprehensive knowledge of FcεRI regulation is thus required. We have identified a functional interaction between FcεRI and CD13 in murine MCs. Antigen-triggered activation of IgE-loaded FcεRI results in cocapping and cointernalization of CD13 and equivalent internalization rates of up to 40%. Cointernalization is not unspecific, because ligand-driven KIT internalization is not accompanied by CD13 internalization. Moreover, antibody-mediated cross-linking of CD13 causes IL-6 production in an FcεRI-dependent manner. These data are indicative of a functional interaction between FcεRI and CD13 on MCs. To determine the role of this interaction, CD13-deficient bone marrow-derived MCs (BMMCs) were analyzed. Intriguingly, antigen stimulation of CD13-deficient BMMCs results in significantly increased degranulation and proinflammatory cytokine production compared to wild-type cells. Furthermore, in a low-dose model of passive systemic anaphylaxis, antigen-dependent decrease in body temperature, reflecting the anaphylactic reaction, is substantially enhanced by the CD13 inhibitor bestatin (-5.9 ± 0.6°C) and by CD13 deficiency (-8.8 ± 0.6°C) in contrast to controls (-1.2 ± 1.97°C). Importantly, bestatin does not aggravate anaphylaxis in CD13-deficient mice. Thus, we have identified CD13 as a novel negative regulator of MC activation in vitro and in vivo

Original language	English
Pages (from-to)	2225-2235
Number of pages	11
Journal	The FASEB Journal
Volume	30
Issue number	6
Early online date	2 Mar 2016
DOIs	https://doi.org/10.1096/fj.201600278
Publication status	Published - Jun 2016

Bibliographical note

The authors acknowledge the excellent technical assistance of Kerstin Fehrenbach (Max Planck Institute for Immunobiology, Freiburg, Germany), Sabrina Schmohl (Department of Dermatology, Eberhard Karls University, Tübingen, Germany), and Yvonne Postma (Department of Dermatology, Eberhard Karls University). The authors are grateful to Dr. Gessner (Hannover Medical School, Hannover, Germany) for providing bone marrow from FcRγ+/+ and FcRγ−/− littermates. This work was supported by the Grants HU794/5-1 (to M.H.), BI696/3-3 (to T.B.), SPP1394 (to M.H. and T.B.), and SFB685 (A06; to T.B.) from the Deutsche Forschungsgemeinschaft, as well as BM-WFaGEN-AU project Austromouse, Austrian Federal Ministry Research and Science, and Austrian Science Fund Grant SFB-F28 (to M.M.).

Keywords

IgE receptor
proinflammatory cytokines
degranulation
passive systemic anaphylaxis
receptor internalization

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10.1096/fj.201600278Licence: Unspecified

Andreas Kolb
- School of Medicine, Medical Sciences & Nutrition, The Rowett Institute of Nutrition and Health - Senior Research Fellow
Person: Academic Related - Research

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@article{c211f7d728f945619c1fcb80b02ec278,

title = "CD13/aminopeptidase N is a negative regulator of mast cell activation",

abstract = "Antigen-induced mast cell (MC) activation via cross-linking of IgE-bound high-affinity receptors for IgE (FcεRI) underlies type I allergy and anaphylactic shock. Comprehensive knowledge of FcεRI regulation is thus required. We have identified a functional interaction between FcεRI and CD13 in murine MCs. Antigen-triggered activation of IgE-loaded FcεRI results in cocapping and cointernalization of CD13 and equivalent internalization rates of up to 40%. Cointernalization is not unspecific, because ligand-driven KIT internalization is not accompanied by CD13 internalization. Moreover, antibody-mediated cross-linking of CD13 causes IL-6 production in an FcεRI-dependent manner. These data are indicative of a functional interaction between FcεRI and CD13 on MCs. To determine the role of this interaction, CD13-deficient bone marrow-derived MCs (BMMCs) were analyzed. Intriguingly, antigen stimulation of CD13-deficient BMMCs results in significantly increased degranulation and proinflammatory cytokine production compared to wild-type cells. Furthermore, in a low-dose model of passive systemic anaphylaxis, antigen-dependent decrease in body temperature, reflecting the anaphylactic reaction, is substantially enhanced by the CD13 inhibitor bestatin (-5.9 ± 0.6°C) and by CD13 deficiency (-8.8 ± 0.6°C) in contrast to controls (-1.2 ± 1.97°C). Importantly, bestatin does not aggravate anaphylaxis in CD13-deficient mice. Thus, we have identified CD13 as a novel negative regulator of MC activation in vitro and in vivo",

keywords = "IgE receptor, proinflammatory cytokines , degranulation, passive systemic anaphylaxis, receptor internalization",

author = "Zotz, {Julia S.} and Florian W{\"o}lbing and Caroline Lassnig and Marlies Kauffmann and Uwe Schulte and Kolb, {Andreas Friedrich} and Bruce Whitelaw and Mathias M{\"u}ller and Tilo Biedermann and Michael Huber",

note = "The authors acknowledge the excellent technical assistance of Kerstin Fehrenbach (Max Planck Institute for Immunobiology, Freiburg, Germany), Sabrina Schmohl (Department of Dermatology, Eberhard Karls University, T{\"u}bingen, Germany), and Yvonne Postma (Department of Dermatology, Eberhard Karls University). The authors are grateful to Dr. Gessner (Hannover Medical School, Hannover, Germany) for providing bone marrow from FcRγ+/+ and FcRγ−/− littermates. This work was supported by the Grants HU794/5-1 (to M.H.), BI696/3-3 (to T.B.), SPP1394 (to M.H. and T.B.), and SFB685 (A06; to T.B.) from the Deutsche Forschungsgemeinschaft, as well as BM-WFaGEN-AU project Austromouse, Austrian Federal Ministry Research and Science, and Austrian Science Fund Grant SFB-F28 (to M.M.).",

year = "2016",

month = jun,

doi = "10.1096/fj.201600278",

language = "English",

volume = "30",

pages = "2225--2235",

journal = "The FASEB Journal",

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publisher = "Wiley",

number = "6",

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TY - JOUR

T1 - CD13/aminopeptidase N is a negative regulator of mast cell activation

AU - Zotz, Julia S.

AU - Wölbing, Florian

AU - Lassnig, Caroline

AU - Kauffmann, Marlies

AU - Schulte, Uwe

AU - Kolb, Andreas Friedrich

AU - Whitelaw, Bruce

AU - Müller, Mathias

AU - Biedermann, Tilo

AU - Huber, Michael

N1 - The authors acknowledge the excellent technical assistance of Kerstin Fehrenbach (Max Planck Institute for Immunobiology, Freiburg, Germany), Sabrina Schmohl (Department of Dermatology, Eberhard Karls University, Tübingen, Germany), and Yvonne Postma (Department of Dermatology, Eberhard Karls University). The authors are grateful to Dr. Gessner (Hannover Medical School, Hannover, Germany) for providing bone marrow from FcRγ+/+ and FcRγ−/− littermates. This work was supported by the Grants HU794/5-1 (to M.H.), BI696/3-3 (to T.B.), SPP1394 (to M.H. and T.B.), and SFB685 (A06; to T.B.) from the Deutsche Forschungsgemeinschaft, as well as BM-WFaGEN-AU project Austromouse, Austrian Federal Ministry Research and Science, and Austrian Science Fund Grant SFB-F28 (to M.M.).

PY - 2016/6

Y1 - 2016/6

N2 - Antigen-induced mast cell (MC) activation via cross-linking of IgE-bound high-affinity receptors for IgE (FcεRI) underlies type I allergy and anaphylactic shock. Comprehensive knowledge of FcεRI regulation is thus required. We have identified a functional interaction between FcεRI and CD13 in murine MCs. Antigen-triggered activation of IgE-loaded FcεRI results in cocapping and cointernalization of CD13 and equivalent internalization rates of up to 40%. Cointernalization is not unspecific, because ligand-driven KIT internalization is not accompanied by CD13 internalization. Moreover, antibody-mediated cross-linking of CD13 causes IL-6 production in an FcεRI-dependent manner. These data are indicative of a functional interaction between FcεRI and CD13 on MCs. To determine the role of this interaction, CD13-deficient bone marrow-derived MCs (BMMCs) were analyzed. Intriguingly, antigen stimulation of CD13-deficient BMMCs results in significantly increased degranulation and proinflammatory cytokine production compared to wild-type cells. Furthermore, in a low-dose model of passive systemic anaphylaxis, antigen-dependent decrease in body temperature, reflecting the anaphylactic reaction, is substantially enhanced by the CD13 inhibitor bestatin (-5.9 ± 0.6°C) and by CD13 deficiency (-8.8 ± 0.6°C) in contrast to controls (-1.2 ± 1.97°C). Importantly, bestatin does not aggravate anaphylaxis in CD13-deficient mice. Thus, we have identified CD13 as a novel negative regulator of MC activation in vitro and in vivo

AB - Antigen-induced mast cell (MC) activation via cross-linking of IgE-bound high-affinity receptors for IgE (FcεRI) underlies type I allergy and anaphylactic shock. Comprehensive knowledge of FcεRI regulation is thus required. We have identified a functional interaction between FcεRI and CD13 in murine MCs. Antigen-triggered activation of IgE-loaded FcεRI results in cocapping and cointernalization of CD13 and equivalent internalization rates of up to 40%. Cointernalization is not unspecific, because ligand-driven KIT internalization is not accompanied by CD13 internalization. Moreover, antibody-mediated cross-linking of CD13 causes IL-6 production in an FcεRI-dependent manner. These data are indicative of a functional interaction between FcεRI and CD13 on MCs. To determine the role of this interaction, CD13-deficient bone marrow-derived MCs (BMMCs) were analyzed. Intriguingly, antigen stimulation of CD13-deficient BMMCs results in significantly increased degranulation and proinflammatory cytokine production compared to wild-type cells. Furthermore, in a low-dose model of passive systemic anaphylaxis, antigen-dependent decrease in body temperature, reflecting the anaphylactic reaction, is substantially enhanced by the CD13 inhibitor bestatin (-5.9 ± 0.6°C) and by CD13 deficiency (-8.8 ± 0.6°C) in contrast to controls (-1.2 ± 1.97°C). Importantly, bestatin does not aggravate anaphylaxis in CD13-deficient mice. Thus, we have identified CD13 as a novel negative regulator of MC activation in vitro and in vivo

KW - IgE receptor

KW - proinflammatory cytokines

KW - degranulation

KW - passive systemic anaphylaxis

KW - receptor internalization

U2 - 10.1096/fj.201600278

DO - 10.1096/fj.201600278

M3 - Article

SN - 0892-6638

VL - 30

SP - 2225

EP - 2235

JO - The FASEB Journal

JF - The FASEB Journal

IS - 6

ER -

CD13/aminopeptidase N is a negative regulator of mast cell activation

Abstract

Bibliographical note

Keywords

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Andreas Kolb

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