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

DOI HANDLE Web Site 54 References Open Access
  • Oda, Yukako
    Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University
  • Takahashi, Chisato
    Department of Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University; Laboratory of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts
  • Harada, Shota
    Laboratory of Human Interface, Graduate School of Systems Life Sciences, Kyushu University
  • Nakamura, Shun
    Cellular and Structural Physiology Laboratory, Advanced Research Institute, Tokyo Medical and Dental University; CeSPIA Inc.
  • Sun, Daxiao
    Max Planck Institute of Molecular Cell Biology and Genetics
  • Kiso, Kazumi
    Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University
  • Urata, Yuko
    Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University
  • Miyachi, Hitoshi
    Reproductive Engineering Team, Institute for Frontier Life and Medical Sciences, Kyoto University
  • Fujiyoshi, Yoshinori
    Cellular and Structural Physiology Laboratory, Advanced Research Institute, Tokyo Medical and Dental University; CeSPIA Inc.
  • Honigmann, Alf
    Max Planck Institute of Molecular Cell Biology and Genetics
  • Uchida, Seiichi
    Laboratory of Human Interface, Graduate School of Systems Life Sciences, Kyushu University
  • Ishihama, Yasushi
    Department of Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Toyoshima, Fumiko
    Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University

Abstract

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.

Journal

  • Science Advances

    Science Advances 7 (47), 2021-11-19

    American Association for the Advancement of Science (AAAS)

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