An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds

Frontiers in Veterinary Science

Veterinary Science

Jing-Jing Jiang¹  Toshiki Sugawara¹  Takeshi Yamasaki²  Rie Hasebe²  Masaaki Murakami³  Yong Bin Teoh⁴  Noriyuki Nagata⁵  Mitsuyoshi Takiguchi⁶  Nozomu Yokoyama⁶  Kensuke Nakamura⁶  Hiroshi Ohta⁷  Yumiko Kagawa⁸  Noboru Sasaki⁹ 

[1] Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan;Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan;Division of Molecular Neuroimmunology, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan;Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan;Division of Molecular Neuroimmunology, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan;Group of Quantum Immunology, Institute for Quantum Life Science, National Institute for Quantum and Radiological Science and Technology (QST), Chiba, Japan;Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan;Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan;Laboratory of Veterinary Internal Medicine, Department of Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan;Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan;Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan;Laboratory of Veterinary Internal Medicine, Department of Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan;Laboratory of Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan;North Lab, Sapporo, Japan;Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan;

关键词: miniature dachshund;    canine;    inflammatory colorectal polyps;    SNP;    thyroglobulin;    inflammation;    IL-6 amplifier;   

DOI  :  10.3389/fvets.2023.1192888

 received in 2023-03-24, accepted in 2023-06-21,  发布年份 2023

来源: Frontiers

【 摘 要 】

Inflammatory colorectal polyp (ICRP) in miniature dachshunds (MDs) is a chronic inflammatory bowel disease (IBD) characterized by granulomatous inflammation that consists of neutrophil infiltration and goblet cell hyperplasia in the colon. Recently, we identified five MD-associated single-nucleotide polymorphisms (SNPs), namely PLG, TCOF1, TG, COL9A2, and COL4A4, by whole-exome sequencing. Here, we investigated whether TG c.4567C>T (p.R1523W) is associated with the ICRP pathology. We found that the frequency of the T/T SNP risk allele was significantly increased in MDs with ICRP. In vitro experiments showed that TG expression in non-immune cells was increased by inducing the IL-6 amplifier with IL-6 and TNF-α. On the other hand, a deficiency of TG suppressed the IL-6 amplifier. Moreover, recombinant TG treatment enhanced the activation of the IL-6 amplifier, suggesting that TG is both a positive regulator and a target of the IL-6 amplifier. We also found that TG expression together with two NF-κB targets, IL6 and CCL2, was increased in colon samples isolated from MDs with the T/T risk allele compared to those with the C/C non-risk allele, but serum TG was not increased. Cumulatively, these results suggest that the T/T SNP is an expression quantitative trait locus (eQTL) of TG mRNA in the colon, and local TG expression triggered by this SNP increases the risk of ICRP in MDs via the IL-6 amplifier. Therefore, TG c.4567C>T is a diagnostic target for ICRP in MDs, and TG-mediated IL-6 amplifier activation in the colon is a possible therapeutic target for ICRP.

【 授权许可】

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Copyright © 2023 Teoh, Jiang, Yamasaki, Nagata, Sugawara, Hasebe, Ohta, Sasaki, Yokoyama, Nakamura, Kagawa, Takiguchi and Murakami.