Comment on hemostatic markers and the sepsis-related organ failure assessment score in patients with disseminated intravascular coagulation in an intensive care unit by Okabayashi et al.

Voves, Claudia; Wuillemin, Walter A.

doi:10.1002/ajh.20343

Cited by 1 publication

(1 citation statement)

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“…GzmA and GzmK have been shown to activate inflammatory responses in macrophages and other cell types 1 and increased levels of GzmA and GzmK have been detected in serum of septic patients suggesting that these proteases could have a role in bacterial sepsis 11 , 12 , 24 . Here, using a mouse model of E. coli induced sepsis, the role of GzmK in an in vivo mouse model of bacterial sepsis has been analysed for the first time.…”

Section: Discussionmentioning

confidence: 99%

Biological relevance of Granzymes A and K during E. coli sepsis

Uranga-Murillo¹,

Tapia²,

Garzón-Tituaña³

et al. 2021

Theranostics

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Aims: Recent in vitro findings suggest that the serine protease Granzyme K (GzmK) may act as a proinflammatory mediator. However, its role in sepsis is unknown. Here we aim to understand the role of GzmK in a mouse model of bacterial sepsis and compare it to the biological relevance of Granzyme A (GzmA). Methods: Sepsis was induced in WT, GzmA -/- and GzmK -/- mice by an intraperitoneal injection of 2x10 8 CFU from E. coli . Mouse survival was monitored during 5 days. Levels of IL-1α, IL-1β, TNFα and IL-6 in plasma were measured and bacterial load in blood, liver and spleen was analyzed. Finally, profile of cellular expression of GzmA and GzmK was analyzed by FACS. Results: GzmA and GzmK are not involved in the control of bacterial infection. However, GzmA and GzmK deficient mice showed a lower sepsis score in comparison with WT mice, although only GzmA deficient mice exhibited increased survival. GzmA deficient mice also showed reduced expression of some proinflammatory cytokines like IL1-α, IL-β and IL-6. A similar result was found when extracellular GzmA was therapeutically inhibited in WT mice using serpinb6b, which improved survival and reduced IL-6 expression. Mechanistically, active extracellular GzmA induces the production of IL-6 in macrophages by a mechanism dependent on TLR4 and MyD88. Conclusions: These results suggest that although both proteases contribute to the clinical signs of E. coli -induced sepsis, inhibition of GzmA is sufficient to reduce inflammation and improve survival irrespectively of the presence of other inflammatory granzymes, like GzmK.

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