Saeed Muhammad A, Ng Garrett Z, Däbritz Jan, Wagner Josef, Judd Louise, Han Jia-Xi, Dhar Poshmaal, Kirkwood Carl D, Sutton Philip
*Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia; †Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, University of Melbourne, Melbourne, Victoria, Australia; ‡Department of Paediatrics, University Medicine Rostock, Rostock, Mecklenburg-Vorpommern, Germany; and §Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
Inflamm Bowel Dis. 2017 Apr;23(4):593-602. doi: 10.1097/MIB.0000000000001045.
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.
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.
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.
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.
蛋白酶激活受体1（PAR1）的蛋白水解切割可对炎症产生强大的下游调节作用。尽管PAR1在整个胃肠道均有表达，且炎症性肠病中激活蛋白酶增加，但PAR1激活对结肠炎的影响仍知之甚少，且此前尚未在儿科疾病中进行研究。
通过定量PCR检测患有活动性中度至重度结肠炎的克罗恩病儿科患者结肠活检组织中PAR1和炎性细胞因子的表达。在鼠柠檬酸杆菌诱导的结肠炎小鼠模型中进一步研究这些临床数据的功能相关性。
患有克罗恩病的儿科患者发炎结肠中PAR1表达显著上调，表达水平与疾病严重程度直接相关。在重症结肠炎患者中，PAR1表达与Th17相关（IL17A、IL22和IL23A）细胞因子独特相关。用致结肠炎的鼠柠檬酸杆菌感染PAR1缺陷（PAR1-/-）小鼠和野生型小鼠，结果显示缺乏PAR1的小鼠疾病严重程度和结肠病理明显减轻。此外，感染PAR1-/-小鼠而非野生型小鼠的结肠中Th17型免疫反应完全消失。最后，研究表明PAR1对于鼠柠檬酸杆菌刺激的巨噬细胞分泌Th17驱动细胞因子IL-23至关重要。
本研究证明了PAR1表达、Th17型免疫与患有克罗恩病的儿科患者以及小鼠鼠柠檬酸杆菌诱导的结肠炎的疾病严重程度之间存在紧密联系。所呈现的数据表明，PAR1通过促进Th17型免疫反应，可能是通过支持IL-23的产生，在人类和小鼠的结肠炎中发挥促炎作用。
