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Protease-activated Receptor 1 plays a proinflammatory role in colitis by promoting Th17-related immunity

Saeed, Muhammad A., Ng, Garrett Z., Däbritz, Jan, Wagner, Josef, Judd, Louise, Han, Jia-Xi, Dhar, Poshmaal, Kirkwood, Carl D. and Sutton, Philip 2017, Protease-activated Receptor 1 plays a proinflammatory role in colitis by promoting Th17-related immunity, Inflammatory bowel diseases, vol. 23, no. 4, pp. 593-602, doi: 10.1097/MIB.0000000000001045.

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Title Protease-activated Receptor 1 plays a proinflammatory role in colitis by promoting Th17-related immunity
Author(s) Saeed, Muhammad A.
Ng, Garrett Z.
Däbritz, Jan
Wagner, Josef
Judd, Louise
Han, Jia-Xi
Dhar, PoshmaalORCID iD for Dhar, Poshmaal orcid.org/0000-0002-2842-007X
Kirkwood, Carl D.
Sutton, Philip
Journal name Inflammatory bowel diseases
Volume number 23
Issue number 4
Start page 593
End page 602
Total pages 10
Publisher Oxford University Press
Place of publication Oxford, Eng.
Publication date 2017-04-01
ISSN 1536-4844
Keyword(s) Adolescent
Animals
Child
Citrobacter rodentium
Colitis
Colon
Crohn's Disease
Cytokines
Disease Models, Animal
Female
Humans
Interleukin-17
Interleukin-23 Subunit p19
Interleukins
Male
Mice
Receptor, PAR-1
Severity of Illness Index
Th17 Cells
Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
Crohn's disease
protease-activated receptor 1
Th17-type immunity
INFLAMMATORY-BOWEL-DISEASE
CITROBACTER-RODENTIUM INFECTION
INNATE LYMPHOID-CELLS
HELICOBACTER-PYLORI
CROHNS-DISEASE
MATRIX METALLOPROTEINASES
DIFFERENTIAL EXPRESSION
THROMBIN GENERATION
Summary BACKGROUND: Proteolytic cleavage of protease-activated receptor 1 (PAR1) can result in potent downstream regulatory effects on inflammation. Although PAR1 is expressed throughout the gastrointestinal tract and activating proteases are increased in inflammatory bowel disease, the effect of PAR1 activation on colitis remains poorly understood, and has not previously been studied in pediatric disease. METHODS: Expression of PAR1 and inflammatory cytokines in colonic biopsies from pediatric patients with Crohn's disease exhibiting active moderate to severe colitis was measured by quantitative PCR. The functional relevance of these clinical data was further studied in a mouse model of Citrobacter rodentium-induced colitis. RESULTS: PAR1 expression was significantly upregulated in the inflamed colons of pediatric patients with Crohn's disease, with expression levels directly correlating to disease severity. In patients with severe colitis, PAR1 expression uniquely correlated with Th17-related (IL17A, IL22, and IL23A) cytokines. Infection of PAR1-deficient (PAR1) and wildtype mice with colitogenic C. rodentium revealed that disease severity and colonic pathology were strongly attenuated in mice lacking PAR1. Furthermore, Th17-type immune response was completely abolished in the colons of infected PAR1 but not wildtype mice. Finally, PAR1 was shown to be essential for secretion of the Th17-driving cytokine IL-23 by C. rodentium-stimulated macrophages. CONCLUSIONS: This study demonstrates a strong link between PAR1 expression, Th17-type immunity, and disease severity in both pediatric patients with Crohn's disease and C. rodentium-induced colitis in mice. The data presented suggest PAR1 exerts a proinflammatory role in colitis in both humans and mice by promoting a Th17-type immune response, potentially by supporting the production of IL-23.
Language eng
DOI 10.1097/MIB.0000000000001045
Field of Research 1103 Clinical Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2017, Crohn’s & Colitis Foundation of America, Inc.
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30112711

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.