Macrophage activation syndrome (MAS) is a life-threatening disorder characterized by
a cytokine storm and multiorgan dysfunction due to excessive immune activation.
Althoughabnormalities of coagulationandfibrinolysis are majorcomponentsofMAS,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