Zoobiquity experiments show the importance of the local MMP9-plasminogen axis in inflammatory bowel diseases in both dogs and patients.

IF 4.8 4区 医学 Q2 IMMUNOLOGY International immunology Pub Date : 2023-07-07 DOI:10.1093/intimm/dxad006
Takeshi Yamasaki, Noriyuki Nagata, Toru Atsumi, Rie Hasebe, Yuki Tanaka, Izuru Ohki, Shimpei Kubota, Yuta Shinohara, Yong Bin Teoh, Nozomu Yokoyama, Noboru Sasaki, Kensuke Nakamura, Hiroshi Ohta, Takehiko Katsurada, Yoshihiro Matsuno, Shintaro Hojyo, Shigeru Hashimoto, Mitsuyoshi Takiguchi, Masaaki Murakami
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引用次数: 1

Abstract

Using a zoobiquity concept, we directly connect animal phenotypes to a human disease mechanism: the reduction of local plasminogen levels caused by matrix metalloproteinase-9 (MMP9) activity is associated with the development of inflammation in the intestines of dogs and patients with inflammatory bowel disease. We first investigated inflammatory colorectal polyps (ICRPs), which are a canine gastrointestinal disease characterized by the presence of idiopathic chronic inflammation, in Miniature Dachshund (MD) and found 31 missense disease-associated SNPs by whole-exome sequencing. We sequenced them in 10 other dog breeds and found five, PLG, TCOF1, TG, COL9A2 and COL4A4, only in MD. We then investigated two rare and breed-specific missense SNPs (T/T SNPs), PLG: c.477G > T and c.478A>T, and found that ICRPs with the T/T SNP risk alleles showed less intact plasminogen and plasmin activity in the lesions compared to ICRPs without the risk alleles but no differences in serum. Moreover, we show that MMP9, which is an NF-κB target, caused the plasminogen reduction and that intestinal epithelial cells expressing plasminogen molecules were co-localized with epithelial cells expressing MMP9 in normal colons with the risk alleles. Importantly, MMP9 expression in patients with ulcerous colitis or Crohn's disease also co-localized with epithelial cells showing enhanced NF-κB activation and less plasminogen expression. Overall, our zoobiquity experiments showed that MMP9 induces the plasminogen reduction in the intestine, contributing to the development of local inflammation and suggesting the local MMP9-plasminogen axis is a therapeutic target in both dogs and patients. Therefore, zoobiquity-type experiments could bring new perspectives for biomarkers and therapeutic targets.

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动物biquity实验表明,局部mmp9 -纤溶酶原轴在犬和患者的炎症性肠病中的重要性。
利用动物异质性的概念,我们直接将动物表型与人类疾病机制联系起来:基质金属蛋白酶-9 (MMP9)活性引起的局部纤溶酶原水平的降低与狗和炎症性肠病患者肠道炎症的发展有关。我们首先研究了炎症性结肠直肠息肉(ICRPs),这是一种以特发性慢性炎症为特征的犬胃肠道疾病,在微型腊肠(MD)中,通过全外显子组测序发现了31个错义疾病相关的snp。我们在其他10个犬种中对它们进行了测序,发现只有在MD中有5个,分别是PLG、TCOF1、TG、COL9A2和COL4A4。然后我们研究了两个罕见且品种特异性的错义SNP (T/T SNP), PLG: c.477G >T和c.478A>T,发现与没有风险等位基因的icrp相比,具有T/T SNP风险等位基因的icrp在病变中显示出更少的完整的纤溶酶原和纤溶酶活性,但在血清中没有差异。此外,我们发现作为NF-κB靶点的MMP9导致纤溶酶原减少,并且在具有风险等位基因的正常结肠中,表达纤溶酶原分子的肠上皮细胞与表达MMP9的上皮细胞共定位。重要的是,溃疡性结肠炎或克罗恩病患者的MMP9表达也与上皮细胞共定位,表现出NF-κB活化增强和纤溶酶原表达减少。总的来说,我们的动物实验表明,MMP9诱导肠内纤溶酶原减少,促进局部炎症的发展,并表明局部MMP9-纤溶酶原轴是犬和患者的治疗靶点。因此,动物实验可以为生物标志物和治疗靶点提供新的视角。
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来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
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