Yamasaki Takeshi, Nagata Noriyuki, Atsumi Toru, Hasebe Rie, Tanaka Yuki, Ohki Izuru, Kubota Shimpei, Shinohara Yuta, Bin Teoh Yong, Yokoyama Nozomu, Sasaki Noboru, Nakamura Kensuke, Ohta Hiroshi, Katsurada Takehiko, Matsuno Yoshihiro, Hojyo Shintaro, Hashimoto Shigeru, Takiguchi Mitsuyoshi, Murakami Masaaki
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Division of Molecular Neuroimmunology, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki, Japan.
Int Immunol. 2023 Jul 7;35(7):313-326. doi: 10.1093/intimm/dxad006.
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.
运用动物与人类共通疾病概念，我们将动物表型直接与人类疾病机制相联系：基质金属蛋白酶-9（MMP9）活性导致的局部纤溶酶原水平降低与犬类及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），这是一种以特发性慢性炎症为特征的犬类胃肠道疾病，在迷你腊肠犬（MD）中通过全外显子测序发现了31个错义疾病相关单核苷酸多态性（SNP）。我们在其他10个犬种中对这些SNP进行测序，发现只有在MD中存在5个，即PLG、TCOF1、TG、COL9A2和COL4A4。然后我们研究了两个罕见且特定品种的错义SNP（T/T SNP），即PLG：c.477G>T和c.478A>T，发现携带T/T SNP风险等位基因的ICRP与不携带风险等位基因的ICRP相比，病变部位的完整纤溶酶原和纤溶酶活性更低，但血清中无差异。此外，我们发现作为NF-κB靶点的MMP9导致了纤溶酶原减少，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表达也与显示NF-κB激活增强和纤溶酶原表达减少的上皮细胞共定位。总体而言，我们的动物与人类共通疾病实验表明，MMP9诱导肠道中纤溶酶原减少，促进局部炎症发展，并提示局部MMP9-纤溶酶原轴是犬类和患者的治疗靶点。因此，动物与人类共通疾病类型的实验可为生物标志物和治疗靶点带来新的视角。
