Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis.
- Wittig BM Medical Clinic 1 (Gastroenterology/Infectiology/Rheumatology), University Medicine Charité, Berlin, Germany.
- Sabat R Interdisciplinary Group of Molecular Immunopathology and Psoriasis Research and Treatment Center, Dermatology/Medical Immunology, University Medicine Charité, Berlin, Germany.
- Holzlöhner P Medical Clinic 1 (Gastroenterology/Infectiology/Rheumatology), University Medicine Charité, Berlin, Germany.
- Witte-Händel E Interdisciplinary Group of Molecular Immunopathology and Psoriasis Research and Treatment Center, Dermatology/Medical Immunology, University Medicine Charité, Berlin, Germany.
- Heilmann K Medical Clinic 1 (Gastroenterology/Infectiology/Rheumatology), University Medicine Charité, Berlin, Germany.
- Witte K Interdisciplinary Group of Molecular Immunopathology and Psoriasis Research and Treatment Center, Dermatology/Medical Immunology, University Medicine Charité, Berlin, Germany.
- Triebus J Interdisciplinary Group of Molecular Immunopathology and Psoriasis Research and Treatment Center, Dermatology/Medical Immunology, University Medicine Charité, Berlin, Germany.
- Tzankov A Institute of Pathology, University Hospital Basel, Basel, Switzerland.
- Laman JD Department of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands.
- Bokemeyer B Gastroenterology Practice, Minden, Germany.
- Terracciano L Institute of Pathology, University Hospital Basel, Basel, Switzerland.
- Schwärzler C Federal Polytechnic University Lausanne (Flow Cytometry Core Facility), Lausanne, Switzerland.
- Kohler H Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
- Volkmer R Institute for Medical Immunology, University Medicine Charité, Berlin, Germany.
- Loddenkemper C Institute of Pathology, University Medicine Charité, Berlin, Germany.
- Wolk K Interdisciplinary Group of Molecular Immunopathology and Psoriasis Research and Treatment Center, Dermatology/Medical Immunology, University Medicine Charité, Berlin, Germany.
- Hoffmann U Medical Clinic 1 (Gastroenterology/Infectiology/Rheumatology), University Medicine Charité, Berlin, Germany.
- Günthert U Institute of Pathology, University Hospital Basel, Basel, Switzerland.
- 2017-11-30
Published in:
- Mucosal immunology. - 2018
Adult
Alternative Splicing
Animals
Cells, Cultured
Coculture Techniques
Colitis
Crohn Disease
Cytokines
Disease Models, Animal
Exons
Female
Forkhead Transcription Factors
Humans
Hyaluronan Receptors
Inflammation Mediators
Macrophages
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Mice, Transgenic
Osteopontin
T-Lymphocyte Subsets
T-Lymphocytes, Regulatory
English
CD44 is a transmembrane molecule appearing in numerous isoforms generated by insertions of alternatively spliced variant exons (CD44v) and having various binding partners. CD44v7 on T cells was proposed to promote colitis by preventing T-cell apoptosis. Here we demonstrate that Cd44v7-deficient T cells - like Cd44 wild-type (Cd44WT) T cells - provoked disease in two different colitis models: the model induced by CD4+CD45RBhigh T-cell transfer into Rag2-deficient mice and a new model based on ovalbumin (OVA)-specific T-cell transfer into Rag-sufficient, OVA-challenged mice. In contrast, CD44v7 absence on macrophages in recipient mice prevented colitis. Prevention was associated with the downregulation of signal transducer and activator of transcription 3 (STAT3)-activating and Foxp3-counteracting interleukin-6 (IL-6), lower numbers of phospho-STAT3-containing lymphocytes, and higher Foxp3+ T-cell counts in the colon. Consequently, the protected colons showed lower IL-12, IL-1β expression, and decreased interferon-γ levels. Importantly, stimulation of T cells by Cd44v7-deficient macrophages induced upregulation of Foxp3 in vitro, while cotransfer of Cd44WT macrophages into Cd44v7-deficient mice reduced Foxp3+ T-cell counts and caused colitis. Accordingly, the CD44v7 ligand osteopontin, whose levels were elevated in Crohn's disease, specifically induced IL-6 in human monocytes, a cytokine also increased in these patients. We suggest macrophage-specific targeting of the CD44v7 pathway as a novel therapeutic option for Crohn's disease.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1038/mi.2017.98
- PMID 29186109
- Persistent URL
- https://sonar.ch/global/documents/232202
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