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

Uranga-Murillo I. ; Tapia E. ; Garzón-Tituaña M. ; Ramirez-Labrada A. ; Santiago L. ; Pesini C. ; Esteban P. ; Roig F.J. ; Galvez E.M. ; Bird P.I. ; Pardo Jimeno, J. (Universidad de Zaragoza) ; Arias M.

Resumen: 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-1a, IL-1ß, TNFa 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-a, IL-ß 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.

Idioma: Inglés

DOI: 10.7150/thno.59418

Año: 2021

Publicado en: Theranostics 11, 20 (2021), 9873-9883
ISSN: 1838-7640

Factor impacto JCR: 11.6 (2021)

Categ. JCR: MEDICINE, RESEARCH & EXPERIMENTAL rank: 13 / 139 = 0.094 (2021) - Q1 - T1

Factor impacto CITESCORE: 16.7 - Pharmacology, Toxicology and Pharmaceutics (Q1) - Medicine (Q1)

Factor impacto SCIMAGO: 2.061 - Pharmacology, Toxicology and Pharmaceutics (miscellaneous) (Q1) - Medicine (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/B29-17R
Financiación: info:eu-repo/grantAgreement/ES/MCIU-AEI/PID2020-113963RB-I00 Desasignar
Financiación: info:eu-repo/grantAgreement/ES/MCIU-AEI/SAF2017-83120-C2-1-R

Tipo y forma: Article (Published version)

Área (Departamento): Área Inmunología (Dpto. Microb.Ped.Radio.Sal.Pú.)