The Institute of Medical Science, The University Of Tokyo

  1. Home
  2. Scientific Papers

Scientific Papers/Award

Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors

Nature communications DOI: 10.1038/ncomms2023
Yosuke Kurashima1,2,3, Takeaki Amiya1,3,4, Tomonori Nochi1, Kumiko Fujisawa1,3, Takeshi Haraguchi5, Hideo Iba5, Hiroko Tsutsui6, Shintaro Sato1,3, Sachiko Nakajima7, Hideki Iijima7, Masato Kubo8,9, Jun Kunisawa1,4 & Hiroshi Kiyono1,2,3,4
1 Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 108-8639, Japan. 2 Graduate School of Medicine, The University of Tokyo, 113-0033, Japan. 3 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 102-0075, Japan. 4 Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Chiba 277-8561, Japan. 5 Division of Host-Parasite Interaction, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 108-8639, Japan. 6 Department of Microbiology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan. 7 Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 565-0871, Japan. 8 Research Center for Allergy and Immunology, RIKEN, Yokohama Institute, Tsurumi, Yokohama, Kanagawa, 230-0045, Japan. 9 Division of Molecular Pathology, Research Institute for Biological Sciences, Tokyo University of Sciences, Chiba 278-0022, Japan.

Mast cells are known effector cells in allergic and inflammatory diseases, but their precise roles in intestinal inflammation remain unknown. Here we show that activation of mast cells in intestinal inflammation is mediated by ATP-reactive P2X7 purinoceptors. We find an increase in the numbers of mast cells expressing P2X7 purinoceptors in the colons of mice with colitis and of patients with Crohn's disease. Treatment of mice with a P2X7 purinoceptor-specific antibody inhibits mast cell activation and subsequent intestinal inflammation. Similarly, intestinal inflammation is ameliorated in mast cell-deficient KitW-sh/W-sh mice, and reconstitution with wild-type, but not P2x7-/- mast cells results in susceptibility to inflammation. ATP-P2X7 purinoceptor-mediated activation of mast cells not only induces inflammatory cytokines, but also chemokines and leukotrienes, to recruit neutrophils and subsequently exacerbate intestinal inflammation. These findings reveal the role of P2X7 purinoceptor-mediated mast cell activation in both the initiation and exacerbation of intestinal inflammation.