A20-deficient mast cells exacerbate inflammatory responses in vivo

Klaus Heger; Kaat Fierens; J Christoph Vahl; Attila Aszodi; Katrin Peschke; Dominik Schenten; Hamida Hammad; Rudi Beyaert; Dieter Saur; Geert van Loo; Axel Roers; Bart N Lambrecht; Mirjam Kool; Marc Schmidt-Supprian

doi:10.1371/journal.pbio.1001762

A20-deficient mast cells exacerbate inflammatory responses in vivo

PLoS Biol. 2014 Jan;12(1):e1001762. doi: 10.1371/journal.pbio.1001762. Epub 2014 Jan 14.

Authors

Affiliations

¹ Molecular Immunology and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
² Laboratory of Immunoregulation, Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium ; Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie, Ghent, Belgium.
³ Department of Surgery, Ludwig Maximilians Universität, Munich, Germany.
⁴ Institute for Immunology, Technische Universität Dresden, Dresden, Germany.
⁵ Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
⁶ Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie, Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
⁷ II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
⁸ Laboratory of Immunoregulation, Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium ; Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie, Ghent, Belgium ; Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

Abstract

Mast cells are implicated in the pathogenesis of inflammatory and autoimmune diseases. However, this notion based on studies in mast cell-deficient mice is controversial. We therefore established an in vivo model for hyperactive mast cells by specifically ablating the NF-κB negative feedback regulator A20. While A20 deficiency did not affect mast cell degranulation, it resulted in amplified pro-inflammatory responses downstream of IgE/FcεRI, TLRs, IL-1R, and IL-33R. As a consequence house dust mite- and IL-33-driven lung inflammation, late phase cutaneous anaphylaxis, and collagen-induced arthritis were aggravated, in contrast to experimental autoimmune encephalomyelitis and immediate anaphylaxis. Our results provide in vivo evidence that hyperactive mast cells can exacerbate inflammatory disorders and define diseases that might benefit from therapeutic intervention with mast cell function.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anaphylaxis / chemically induced
Anaphylaxis / immunology*
Anaphylaxis / metabolism
Anaphylaxis / pathology
Animals
Arthritis, Experimental / chemically induced
Arthritis, Experimental / immunology*
Arthritis, Experimental / metabolism
Arthritis, Experimental / pathology
Collagen Type II / administration & dosage
Cysteine Endopeptidases
DNA-Binding Proteins / deficiency*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / immunology
Dinitrophenols / administration & dosage
Encephalomyelitis, Autoimmune, Experimental / chemically induced
Encephalomyelitis, Autoimmune, Experimental / immunology*
Encephalomyelitis, Autoimmune, Experimental / metabolism
Encephalomyelitis, Autoimmune, Experimental / pathology
Gene Expression
Immunoglobulin E / genetics
Immunoglobulin E / immunology
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
Interleukins / genetics
Interleukins / immunology
Intracellular Signaling Peptides and Proteins / deficiency*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / immunology
Lung / immunology
Lung / metabolism
Lung / pathology
Male
Mast Cells / immunology*
Mast Cells / metabolism
Mast Cells / pathology
Mice
Mice, Transgenic
Myelin-Oligodendrocyte Glycoprotein / administration & dosage
NF-kappa B / genetics
NF-kappa B / immunology
Peptide Fragments / administration & dosage
Pneumonia / chemically induced
Pneumonia / immunology
Pneumonia / metabolism
Pneumonia / pathology
Pyroglyphidae / immunology
Receptors, IgE / genetics
Receptors, IgE / immunology
Receptors, Interleukin / genetics
Receptors, Interleukin / immunology
Receptors, Interleukin-1 / genetics
Receptors, Interleukin-1 / immunology
Serum Albumin, Bovine / administration & dosage
Toll-Like Receptors / genetics
Toll-Like Receptors / immunology
Tumor Necrosis Factor alpha-Induced Protein 3
Ubiquitin-Protein Ligases / deficiency*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / immunology

Substances

Collagen Type II
DNA-Binding Proteins
Dinitrophenols
Il1rl1 protein, mouse
Il33 protein, mouse
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
Interleukins
Intracellular Signaling Peptides and Proteins
Myelin-Oligodendrocyte Glycoprotein
NF-kappa B
Peptide Fragments
Receptors, IgE
Receptors, Interleukin
Receptors, Interleukin-1
Toll-Like Receptors
dinitrophenyl-bovine serum albumin
myelin oligodendrocyte glycoprotein (35-55)
Serum Albumin, Bovine
Immunoglobulin E
Ubiquitin-Protein Ligases
Tumor Necrosis Factor alpha-Induced Protein 3
Cysteine Endopeptidases
Tnfaip3 protein, mouse

Grants and funding

This work was supported by an Emmy Noether grant and a Fond der chemischen Industrie grant to MS-S. KH and JCV were supported by the Boehringer Ingelheim Fonds and the Ernst Schering Foundation, respectively. MK was supported by a Veni grant from the Netherlands Organisation for Scientific Research and a FP7 Marie Curie IEF grant. KF was supported by a grant of FWO Flanders; and BNL was supported by an ERC consolidator grant, a University of Ghent MRP grant (GROUP-ID), and by grants of FWO Flanders. RB is supported by a University of Ghent GOA grant and by grants from the IWT, FWO-Flanders, and IAP. DS was supported by the DFG (SA 1374/1-2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.