dhar-proteaseactivated-2017.pdf (1.02 MB)
Protease-activated Receptor 1 plays a proinflammatory role in colitis by promoting Th17-related immunity
journal contribution
posted on 2017-04-01, 00:00 authored by Muhammad A Saeed, Garrett Z Ng, Jan Däbritz, Josef Wagner, Louise Judd, Jia-Xi Han, Poshmaal DharPoshmaal Dhar, Carl D Kirkwood, Philip SuttonBACKGROUND: 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.
History
Journal
Inflammatory bowel diseasesVolume
23Issue
4Pagination
593 - 602Publisher
Oxford University PressLocation
Oxford, Eng.Publisher DOI
eISSN
1536-4844Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2017, Crohn’s & Colitis Foundation of America, Inc.Usage metrics
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AdolescentAnimalsChildCitrobacter rodentiumColitisColonCrohn DiseaseCytokinesDisease Models, AnimalFemaleHumansInterleukin-17Interleukin-23 Subunit p19InterleukinsMaleMiceReceptor, PAR-1Severity of Illness IndexTh17 CellsScience & TechnologyLife Sciences & BiomedicineGastroenterology & HepatologyCrohn's diseaseprotease-activated receptor 1Th17-type immunityINFLAMMATORY-BOWEL-DISEASECITROBACTER-RODENTIUM INFECTIONINNATE LYMPHOID-CELLSHELICOBACTER-PYLORICROHNS-DISEASEMATRIX METALLOPROTEINASESDIFFERENTIAL EXPRESSIONTHROMBIN GENERATION
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