doi:10.7150/thno.59418engUranga-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.Arias M.Biological relevance of Granzymes A and K during E. coli sepsisART-2021-127144Aims: 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.2021http://zaguan.unizar.es/record/15134910.7150/thno.59418http://zaguan.unizar.es/record/151349oai:zaguan.unizar.es:151349info:eu-repo/grantAgreement/ES/DGA/B29-17Rinfo:eu-repo/grantAgreement/ES/MCIU-AEI/PID2020-113963RB-I00 Desasignarinfo:eu-repo/grantAgreement/ES/MCIU-AEI/SAF2017-83120-C2-1-RTheranostics 11, 20 (2021), 9873-9883byhttps://creativecommons.org/licenses/by/4.0/deed.esinfo:eu-repo/semantics/openAccess