Exacerbation of non‐steroidal anti‐inflammatory drug‐induced enteropathy in C‐C chemokine receptor type 7‐deficient mice

• Published in: Journal of gastroenterology and hepatology 2022-08, Vol.37 (8), p.1561-1570
• Main Authors: Yamaguchi, Toshio, Iijima, Hideki, Yoshihara, Takeo, Tani, Mizuki, Otake, Yuriko, Iwatani, Shuko, Amano, Takahiro, Tashiro, Taku, Kurahashi, Tomohide, Inoue, Takanori, Tsujii, Yoshiki, Hayashi, Yoshito, Inoue, Takahiro, Motooka, Daisuke, Nakamura, Shota, Shinzaki, Shinichiro, Takehara, Tetsuo
• Format: Article
• Language: English
• Subjects: CC chemokine receptors; CCR7 protein; CD103 antigen; Cell migration; Chemokine receptors; Chemokines; Dendritic cells; Epithelial cells; Gene expression; IL‐22 binding protein; Immunoregulation; Immunosuppressive agents; Indomethacin; Inflammation; Injection; Lymphocytes T; migration; Mucosa; Nonsteroidal anti-inflammatory drugs; NSAIDs C‐C chemokine receptor type 7; Phenotypes; Rodents; Small intestine
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/jgh.15868

Background and Aim Non‐steroidal anti‐inflammatory drugs (NSAIDs) induce intestinal enteropathy and the pathophysiology is related to immune‐mediated mechanisms. We aimed to investigate the role of C‐C chemokine receptor type 7 (CCR7) which regulates immune cell migration in NSAID‐induced enteropathy. Methods Injury of the small intestine was evaluated 24 h after the subcutaneous injection of indomethacin in CCR7‐deficient (Ccr7−/−) and wild‐type (WT) mice. The cellular profile and cytokine production in intestinal cells were analyzed. Indomethacin‐induced enteropathy was evaluated in mice adoptively transferred with CD103+ dendritic cells (DCs) from Ccr7−/− or WT mice. Results Indomethacin induced more severe intestinal injury in Ccr7−/− mice than in WT mice. The major inflammatory cytokines were not increased and the proportion of regulatory T cells following indomethacin injection was not decreased in Ccr7−/− mice compared with WT mice. The expression of interleukin (IL)‐22 binding protein (IL‐22BP), which inhibits IL‐22 activity, was significantly higher in CD103+ DCs from Ccr7−/− mice than those from WT mice. Mice adoptively transferred with CD103+ DCs isolated from Ccr7−/− mice exhibited more severe intestinal injury following indomethacin injection compared with those adoptively transferred with CD103+ DCs of WT mice. Ccr7−/− mice injected with indomethacin showed a significant reduction in regenerating islet‐derived 1 (Reg1) mRNA expression, which is regulated by IL‐22, in intestinal epithelial cells. Conclusions C‐C chemokine receptor type 7 deficiency exacerbated NSAID‐induced enteropathy in association with an altered phenotype of CD103+ DCs that produces IL‐22BP. CCR7 contributes to protect the small intestine from NSAID‐induced mucosal injury.