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  4. Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis
 
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research article

Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis

Wittig, B. M.
•
Sabat, R.  
•
Holzloehner, P.
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May 1, 2018
Mucosal Immunology

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 (Cd44(WT)) T cells provoked disease in two different colitis models: the model induced by CD4thornCD45RB high 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 Foxp3thorn T-cell counts in the colon. Consequently, the protected colons showed lower IL-12, IL-1 beta expression, and decreased interferon-gamma levels. Importantly, stimulation of T cells by Cd44v7-deficient macrophages induced upregulation of Foxp3 in vitro, while cotransfer of Cd44(WT) macrophages into Cd44v7-deficient mice reduced Foxp(3+) 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.

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Type
research article
DOI
10.1038/mi.2017.98
Web of Science ID

WOS:000433899600023

Author(s)
Wittig, B. M.
•
Sabat, R.  
•
Holzloehner, P.
•
Witte-Haendel, E.
•
Heilmann, K.
•
Witte, K.
•
Triebus, J.
•
Tzankov, A.
•
Laman, J. D.
•
Bokemeyer, B.
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Date Issued

2018-05-01

Publisher

NATURE PUBLISHING GROUP

Published in
Mucosal Immunology
Volume

11

Issue

3

Start page

846

End page

860

Subjects

Immunology

•

inflammatory-bowel-disease

•

regulatory t-cells

•

growth-factor-beta

•

crohns-disease

•

proinflammatory cytokines

•

antimicrobial defense

•

cutting edge

•

mice

•

homeostasis

•

il-22

Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
THEOS  
MMSPL  
Available on Infoscience
December 13, 2018
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/152704
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