Discovery of anti-inflammatory physiological peptides that promote tissue repair by reinforcing epithelial barrier formation

• Published in: Science advances Vol. 7; no. 47; p. eabj6895
• Main Authors: Oda, Yukako, Takahashi, Chisato, Harada, Shota, Nakamura, Shun, Sun, Daxiao, Kiso, Kazumi, Urata, Yuko, Miyachi, Hitoshi, Fujiyoshi, Yoshinori, Honigmann, Alf, Uchida, Seiichi, Ishihama, Yasushi, Toyoshima, Fumiko
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 19.11.2021
• Subjects: Biomedicine and Life Sciences; Cell Biology; Health and Medicine; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abj6895

C-terminal alpha 1-antitrypsin peptides induce tight junction formation by activating G protein G13. Epithelial barriers that prevent dehydration and pathogen invasion are established by tight junctions (TJs), and their disruption leads to various inflammatory diseases and tissue destruction. However, a therapeutic strategy to overcome TJ disruption in diseases has not been established because of the lack of clinically applicable TJ-inducing molecules. Here, we found TJ-inducing peptides (JIPs) in mice and humans that corresponded to 35 to 42 residue peptides of the C terminus of alpha 1-antitrypsin (A1AT), an acute-phase anti-inflammatory protein. JIPs were inserted into the plasma membrane of epithelial cells, which promoted TJ formation by directly activating the heterotrimeric G protein G13. In a mouse intestinal epithelial injury model established by dextran sodium sulfate, mouse or human JIP administration restored TJ integrity and strongly prevented colitis. Our study has revealed TJ-inducing anti-inflammatory physiological peptides that play a critical role in tissue repair and proposes a previously unidentified therapeutic strategy for TJ-disrupted diseases.