Open AccessBiological relevance of Granzymes A and K during E. coli sepsis
Author(s) -
Iratxe Uranga-Murillo,
Elena Tapia,
Marcela Garzón-Tituaña,
Ariel Ramírez-Labrada,
Llipsy Santiago,
Cecilia Pesini,
Patricia Esteban,
Francisco J. Roig,
Eva M. Gálvez,
Phillip I. Bird,
Julián Pardo,
Maykel Arias
Publication year - 2021
Publication title -
theranostics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.689
H-Index - 97
ISSN - 1838-7640
DOI - 10.7150/thno.59418
Subject(s) - granzyme a , granzyme , proinflammatory cytokine , sepsis , extracellular , proteases , immunology , inflammation , tlr4 , biology , chemistry , granzyme b , microbiology and biotechnology , immune system , perforin , t cell , enzyme , biochemistry , cd8
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.