Zoobiquity experiments show the importance of the local MMP9-plasminogen axis in inflammatory bowel diseases in both dogs and patients.
Zoobiquity experiments show the importance of the local MMP9-plasminogen axis in inflammatory bowel diseases in both dogs and patients.
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Zoobiquity 实验表明局部 MMP9-纤溶酶原轴在狗和患者炎症性肠病中的重要性。
DOI：
10.1093/intimm/dxad006
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发表时间：
2023
影响因子：
4.4
通讯作者：
Shig
中科院分区：
文献类型：
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作者：
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;Shig
使用动物传染性概念，我们直接将动物表型与人类疾病机制联系起来：由基质金属蛋白酶9（MMP 9）活性引起的局部纤溶酶原水平降低与犬和炎症性肠病患者肠道炎症的发展相关。我们首先研究了炎性结直肠息肉（ICRP），这是一种以存在特发性慢性炎症为特征的犬胃肠道疾病，在小型腊肠犬（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个品种的狗中进行了测序，发现了5个，PLG，TCOF 1，TG，COL 9A 2和COL 4A 4，仅在MD中。然后，我们研究了两种罕见的和品种特异性的错义SNP（T/T SNP），PLG：c.477G > T和c.478A>T，并且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在病变中显示出较少的完整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，MMP 9，这是一个NF-κB的目标，造成纤溶酶原减少，肠上皮细胞表达纤溶酶原分子与上皮细胞表达MMP 9在正常结肠与风险等位基因共定位。重要的是，溃疡性结肠炎或克罗恩病患者的MMP 9表达也与上皮细胞共定位，显示增强的NF-κB活化和较少的纤溶酶原表达。总之，我们的动物感染实验表明，MMP 9诱导肠中纤溶酶原减少，有助于局部炎症的发展，并表明局部MMP 9-纤溶酶原轴是犬和患者的治疗靶点。因此，动物亲和性类型的实验可以为生物标志物和治疗靶点带来新的前景。
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, COL9A2andCOL4A4, 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.