000151349 001__ 151349 000151349 005__ 20251017144626.0 000151349 0247_ $$2doi$$a10.7150/thno.59418 000151349 0248_ $$2sideral$$a127144 000151349 037__ $$aART-2021-127144 000151349 041__ $$aeng 000151349 100__ $$aUranga-Murillo I. 000151349 245__ $$aBiological relevance of Granzymes A and K during E. coli sepsis 000151349 260__ $$c2021 000151349 5060_ $$aAccess copy available to the general public$$fUnrestricted 000151349 5203_ $$aAims: 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. 000151349 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B29-17R$$9info:eu-repo/grantAgreement/ES/MCIU-AEI/PID2020-113963RB-I00 Desasignar$$9info:eu-repo/grantAgreement/ES/MCIU-AEI/SAF2017-83120-C2-1-R 000151349 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es 000151349 590__ $$a11.6$$b2021 000151349 591__ $$aMEDICINE, RESEARCH & EXPERIMENTAL$$b13 / 139 = 0.094$$c2021$$dQ1$$eT1 000151349 592__ $$a2.061$$b2021 000151349 593__ $$aPharmacology, Toxicology and Pharmaceutics (miscellaneous)$$c2021$$dQ1 000151349 593__ $$aMedicine (miscellaneous)$$c2021$$dQ1 000151349 594__ $$a16.7$$b2021 000151349 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000151349 700__ $$aTapia E. 000151349 700__ $$aGarzón-Tituaña M. 000151349 700__ $$aRamirez-Labrada A. 000151349 700__ $$aSantiago L. 000151349 700__ $$aPesini C. 000151349 700__ $$aEsteban P. 000151349 700__ $$aRoig F.J. 000151349 700__ $$aGalvez E.M. 000151349 700__ $$aBird P.I. 000151349 700__ $$0(orcid)0000-0003-0154-0730$$aPardo Jimeno, J.$$uUniversidad de Zaragoza 000151349 700__ $$aArias M. 000151349 7102_ $$11011$$2566$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Inmunología 000151349 773__ $$g11, 20 (2021), 9873-9883$$pTHERANOSTICS$$tTheranostics$$x1838-7640 000151349 8564_ $$s1312433$$uhttps://zaguan.unizar.es/record/151349/files/texto_completo.pdf$$yVersión publicada 000151349 8564_ $$s2289517$$uhttps://zaguan.unizar.es/record/151349/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000151349 909CO $$ooai:zaguan.unizar.es:151349$$particulos$$pdriver 000151349 951__ $$a2025-10-17-14:24:05 000151349 980__ $$aARTICLE