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.

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

Grant support

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.