Pharmacological targeting of plasmin prevents lethality in a murine model of macrophage activation syndrome

Hiroshi Shimazu, Shinya Munakata, Yoshihiko Tashiro, Yousef Salama, Douaa Dhahri, Salita Eiamboonsert, Yasunori Ota, Haruo Onoda, Yuko Tsuda, Yoshio Okada, Hiromitsu Nakauchi, Beate Heissig and Koichi Hattori

Key points

  • Plasminogen/plasmin is excessively activated in murine model of fulminant MAS.

  • The genetic or pharmacological inhibition of plasminogen/plasmin counteracted cytokine storm and tissue damage in fulminant MAS.


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.

  • Submitted September 7, 2016.
  • Accepted March 10, 2017.