A20-deficient mast cells exacerbate inflammatory responses in vivo.
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.
Molecular Immunology and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
Klaus
K
Heger
Laboratory of Immunoregulation, Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium ; Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie, Ghent, Belgium.
Kaat
K
Fierens
Molecular Immunology and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
J Christoph
JC
Vahl
Department of Surgery, Ludwig Maximilians Universität, Munich, Germany.
Attila
A
Aszodi
Institute for Immunology, Technische Universität Dresden, Dresden, Germany.
Katrin
K
Peschke
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Dominik
D
Schenten
Laboratory of Immunoregulation, Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium ; Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie, Ghent, Belgium.
Hamida
H
Hammad
Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie, Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Rudi
R
Beyaert
II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Dieter
D
Saur
Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie, Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Geert
G
van Loo
Institute for Immunology, Technische Universität Dresden, Dresden, Germany.
Axel
A
Roers
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.
Bart N
BN
Lambrecht
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.
Mirjam
M
Kool
Molecular Immunology and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
Marc
M
Schmidt-Supprian
D000707:Anaphylaxis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D024043:Collagen Type II / Q000008:administration & dosage; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D004140:Dinitrophenols / Q000008:administration & dosage; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000008:administration & dosage; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D039981:Pyroglyphidae / Q000276:immunology; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology; D012710:Serum Albumin, Bovine / Q000008:administration & dosage; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology
D024043:Collagen Type II; D004268:DNA-Binding Proteins; D004140:Dinitrophenols; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D016328:NF-kappa B; D010446:Peptide Fragments; D017455:Receptors, IgE; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C034638:dinitrophenyl-bovine serum albumin; C445081:myelin oligodendrocyte glycoprotein (35-55); D012710:Serum Albumin, Bovine; D007073:Immunoglobulin E; D044767:Ubiquitin-Protein Ligases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse