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

Abstract

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.

Blood-derived plasminogen drives brain inflammation and plaque deposition in a mouse model of Alzheimer’s disease

“…Monocytes and monocytic cells have binding sites for PLG (8), and PL is a direct activator of these cells (9). When PL is depleted pharmacologically in a model of excessive immune activation, mice have higher survival rates and less inflammation, suggesting that PL plays a key role in production of inflammatory cytokines and chemokines (10). In cases where PL is generated in excess in inflamed tissues, PL is able to activate the classic complement cascade (11)(12)(13), which is involved in innate immunity, and this activation can lead to vasodilation and vascular permeability (14).…”

Nrf2 Activator PB125®as a Potential Therapeutic Agent Against COVID-19

“…Macrophage activation syndrome (MAS) is a life-threatening disorder characterized by a cytokine storm and multiorgan dysfunction due to excessive immune activation. In a mouse model of MAS, Shimazu et al saw a similar prevention in lethality, concluding that plasmin regulates the influx of inflammatory cells and the production of inflammatory cytokines/chemokines [30]. Plasminogen has also been implicated in activation of astrocytes to produce an array of proinflammatory cytokines [45].…”

“…In a study of 23 subjects with homozygous mutations in the PLG gene and little or no detectable plasmin, 96% had clinical inflammation of the conjunctivae (ligneous conjunctivitis) but 0% had experienced venous thrombosis [41]. New roles, however, have been recognized for plasmin regarding cytokine release [30,[42][43][44][45]. A "cytokine storm syndrome" is a form of systemic inflammatory response that can be triggered by a variety of factors such as severe infections.…”

“…The cytokine LIF, an important antiviral cellular response to viral infection [28,29], was up regulated 6.6-fold by PB125. Because of recent evidence that plasmin can trigger substantial proinflammatory release of cytokines [30], we examined the effect of PB125 on plasminogen (PLG) mRNA expression, finding it to be down regulated by -1.9-fold. Thus, all six of these gene regulatory effects of PB125 would appear to counter viral attempts to enter the cell and to usurp control of oxidative stress response.…”

Plasmin regulation of acute cytokine storm

“…1 M acrophage activation syndrome (MAS) is a life-threatening complication associated with systemic juvenile idiopathic arthritis or with adult-onset Still disease. 2 This syndrome has several attributes common to hemophagocytic lymphohistiocytosis (HLH), because both of these life-threatening conditions are characterized by a supraphysiological elevation of cytokines, an increase in inflammation, multiorgan dysfunction, and death.…”