Pharmacological targeting of plasmin prevents lethality in a murine model of macrophage activation syndrome.
Macrophage activation syndrome (MAS) is a life-threatening disorder characterized by a cytokine storm and multiorgan dysfunction due to excessive immune activation. Although abnormalities of coagulation and fibrinolysis are major components of MAS, the role of the fibrinolytic system and its key player, plasmin, in the development of MAS remains to be solved. We established a murine model of fulminant MAS by repeated injections of Toll-like receptor-9 (TLR-9) agonist and d-galactosamine (DG) in immunocompetent mice. We found plasmin was excessively activated during the progression of fulminant MAS in mice. Genetic and pharmacological inhibition of plasmin counteracted MAS-associated lethality and other related symptoms. We show that plasmin regulates the influx of inflammatory cells and the production of inflammatory cytokines/chemokines. Collectively, our findings identify plasmin as a decisive checkpoint in the inflammatory response during MAS and a potential novel therapeutic target for MAS.
Center for Stem Cell Biology and Regenerative Medicine.|Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, and.
Hiroshi
H
Shimazu
Center for Stem Cell Biology and Regenerative Medicine.
Shinya
S
Munakata
Center for Stem Cell Biology and Regenerative Medicine.
Yoshihiko
Y
Tashiro
Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, and.
Yousef
Y
Salama
Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, and.
Douaa
D
Dhahri
Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, and.
Salita
S
Eiamboonsert
Department of Diagnostic Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yasunori
Y
Ota
Department of Diagnostic Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Haruo
H
Onoda
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan; and.
Yuko
Y
Tsuda
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan; and.
Yoshio
Y
Okada
Center for Stem Cell Biology and Regenerative Medicine.
Hiromitsu
H
Nakauchi
Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, and.|Atopy Center and.
Beate
B
Heissig
Center for Stem Cell Biology and Regenerative Medicine.|Center for Genome and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Koichi
K
Hattori
D000818:Animals; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000235:genetics / Q000378:metabolism*; D005688:Galactosamine / Q000494:pharmacology; D006801:Humans; D055501:Macrophage Activation Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000067996:RAW 264.7 Cells; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000235:genetics / Q000378:metabolism
C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D005688:Galactosamine; D005341:Fibrinolysin