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|Title:||Biological relevance of Granzymes A and K during E. coli sepsis|
Roig, Francisco J.
Galvez, Eva M.
Bird, Phillip Ian
|Keywords:||Granzyme K; Granzyme A; Bacterial sepsis; Inflammation|
|Publisher:||IVYSPRING INT PUBLPO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA|
|Citation:||Uranga-Murillo I, Tapia E, Garzón-Tituaña M, Ramirez-Labrada A, Santiago L, Pesini C, Esteban P, Roig FJ, Galvez EM, Bird PI, Pardo J, Arias M. Biological relevance of Granzymes A and K during E. coli sepsis. Theranostics 2021; 11(20):9873-9883. doi:10.7150/thno.59418. Available from https://www.thno.org/v11p9873.htm|
|Abstract:||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 2x108 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.|
|Appears in Collections:||Artículos de revistas|
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