Shinya Munakata1, Yoshihiko Tashiro1, Chiemi Nishida2, Aki Sato3, Hiromitsu Komiyama4, Hiroshi Shimazu3, Douaa Dhahri5, Yousef Salama5, Salita Eiamboonsert5, Kazuyoshi Takeda6, Hideo Yagita6, Yuko Tsuda7, Yoshio Okada7, Hiromitsu Nakauchi3, Kazuhiro Sakamoto8, Beate Heissig9, Koichi Hattori10. 1. Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Department of Coloproctological Surgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan. 2. Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan. 3. Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan. 4. Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Department of Coloproctological Surgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. 5. Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan. 6. Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. 7. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Ikawadani-cho, Nishi-ku, Kobe, Japan. 8. Department of Coloproctological Surgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. 9. Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Atopy (Allergy) Center, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. 10. Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Atopy (Allergy) Center, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. Electronic address: khattori@ims.u-tokyo.ac.jp.
Abstract
BACKGROUND & AIMS: Activated proteases such as plasmin and matrix metalloproteinases (MMPs) are activated in intestinal tissues of patients with active inflammatory bowel diseases. We investigated the effect of plasmin on the progression of acute colitis. METHODS: Colitis was induced in Mmp9(-/-), Plg(-/-), and C57BL/6 (control) mice by the administration of dextran sulfate sodium, trinitrobenzene sulfonic acid, or CD40 antibody. Plasmin was inhibited in control mice by intraperitoneal injection of YO-2, which blocks its active site. Mucosal and blood samples were collected and analyzed by reverse-transcription polymerase chain reaction and immunohistochemical analyses, as well as for mucosal inflammation and levels of cytokines and chemokines. RESULTS: Circulating levels of plasmin were increased in mice with colitis, compared with controls. Colitis did not develop in control mice injected with YO-2 or in Plg(-/-) mice. Colons from these mice had reduced infiltration of Gr1+ neutrophils and F4/80+ macrophages, and reduced levels of inflammatory cytokines and chemokines. Colonic inflammation and colitis induction required activation of endogenous MMP9. After colitis induction, mice given YO-2, Plg(-/-) mice, and Mmp9(-/-) mice had reduced serum levels of tumor necrosis factor and C-X-C motif chemokine ligand 5, compared with control mice. CONCLUSIONS: In mice, plasmin induces a feedback mechanism in which activation of the fibrinolytic system promotes the development of colitis via activation of MMP9 or proteolytic enzymes. The proteolytic environment stimulates the influx of myeloid cells into the colonic epithelium and the production of tumor necrosis factor and C-X-C motif chemokine ligand 5. In turn, myeloid CD11b+ cells release the urokinase plasminogen activator, which accelerates plasmin production. Disruption of the plasmin-induced chronic inflammatory circuit therefore might be a strategy for colitis treatment.
BACKGROUND & AIMS: Activated proteases such as plasmin and matrix metalloproteinases (MMPs) are activated in intestinal tissues of patients with active inflammatory bowel diseases. We investigated the effect of plasmin on the progression of acute colitis. METHODS:Colitis was induced in Mmp9(-/-), Plg(-/-), and C57BL/6 (control) mice by the administration of dextran sulfate sodium, trinitrobenzene sulfonic acid, or CD40 antibody. Plasmin was inhibited in control mice by intraperitoneal injection of YO-2, which blocks its active site. Mucosal and blood samples were collected and analyzed by reverse-transcription polymerase chain reaction and immunohistochemical analyses, as well as for mucosal inflammation and levels of cytokines and chemokines. RESULTS: Circulating levels of plasmin were increased in mice with colitis, compared with controls. Colitis did not develop in control mice injected with YO-2 or in Plg(-/-) mice. Colons from these mice had reduced infiltration of Gr1+ neutrophils and F4/80+ macrophages, and reduced levels of inflammatory cytokines and chemokines. Colonic inflammation and colitis induction required activation of endogenous MMP9. After colitis induction, mice given YO-2, Plg(-/-) mice, and Mmp9(-/-) mice had reduced serum levels of tumor necrosis factor and C-X-C motif chemokine ligand 5, compared with control mice. CONCLUSIONS: In mice, plasmin induces a feedback mechanism in which activation of the fibrinolytic system promotes the development of colitis via activation of MMP9 or proteolytic enzymes. The proteolytic environment stimulates the influx of myeloid cells into the colonic epithelium and the production of tumor necrosis factor and C-X-C motif chemokine ligand 5. In turn, myeloid CD11b+ cells release the urokinase plasminogen activator, which accelerates plasmin production. Disruption of the plasmin-induced chronic inflammatory circuit therefore might be a strategy for colitis treatment.
Authors: Wayne A Schroder; Thiago D Hirata; Thuy T Le; Joy Gardner; Glen M Boyle; Jonathan Ellis; Eri Nakayama; Dilan Pathirana; Helder I Nakaya; Andreas Suhrbier Journal: Sci Rep Date: 2019-08-27 Impact factor: 4.379