151349 20251017144626.0 doi 10.7150/thno.59418 sideral 127144 ART-2021-127144 eng Uranga-Murillo I. Biological relevance of Granzymes A and K during E. coli sepsis 2021 Access copy available to the general public Unrestricted 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. info:eu-repo/grantAgreement/ES/DGA/B29-17R info:eu-repo/grantAgreement/ES/MCIU-AEI/PID2020-113963RB-I00 Desasignar info:eu-repo/grantAgreement/ES/MCIU-AEI/SAF2017-83120-C2-1-R info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es 11.6 2021 MEDICINE, RESEARCH & EXPERIMENTAL 13 / 139 = 0.094 2021 Q1 T1 2.061 2021 Pharmacology, Toxicology and Pharmaceutics (miscellaneous) 2021 Q1 Medicine (miscellaneous) 2021 Q1 16.7 2021 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 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 (orcid)0000-0003-0154-0730 Arias M. 1011 566 Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Área Inmunología 11, 20 (2021), 9873-9883 THERANOSTICS Theranostics 1838-7640 1312433 http://zaguan.unizar.es/record/151349/files/texto_completo.pdf Versión publicada 2289517 http://zaguan.unizar.es/record/151349/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:151349 articulos driver 2025-10-17-14:24:05 ARTICLE