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

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.