title: Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking.
abstract: The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction.
authors.affiliation: Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Sato
authors.affiliation: 1] Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan [2] Department of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Nishida
authors.affiliation: Department of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sato-Kusubata
authors.affiliation: Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ishihara
authors.affiliation: Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tashiro
authors.affiliation: Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Gritli
authors.affiliation: Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shimazu
authors.affiliation: Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Munakata
authors.affiliation: Department of Immunology, Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Department of Immunology, Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tsuda
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Hematology and Oncology, Center for Stem Cell Biology and Regenerative Medicine, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tojo
authors.affiliation: Department of Hematology and Oncology, Center for Stem Cell Biology and Regenerative Medicine, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nakauchi
authors.affiliation: Department of Hematology and Oncology, Center for Stem Cell Biology and Regenerative Medicine, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: 1] Department of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan [2] Department of Immunology, Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: B
authors.initials: B
authors.lastname: Heissig
authors.affiliation: 1] Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan [2] Department of Immunology, Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hattori
mesh_terms: D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D002460:Cell Line; D017931:DNA Primers; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005341:Fibrinolysin / Q000037:antagonists & inhibitors*; D006086:Graft vs Host Disease / Q000201:enzymology / Q000401:mortality / Q000517:prevention & control*; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index
chemical_list: D017931:DNA Primers; D018836:Inflammation Mediators; D005341:Fibrinolysin; D020780:Matrix Metalloproteinase 9