| Zdroj: |
Beltrán García, Jesús Osca Verdegal, Rebeca Pérez Cremades, Daniel Novella, Susana Hermenegildo, Carlos Pallardó Calatayud, Federico Vicente García Giménez, José Luis 2022 Extracellular histones activate endothelial NLRP3 inflammasome and are associated with a severe sepsis phenotype. Journal Of Inflammation Research 15 4217 4238 |
| Popis: |
Jesús Beltrán-GarcÃa,1â 3 Rebeca Osca-Verdegal,1,3 Daniel Pérez-Cremades,2,3 Susana Novella,2,3 Carlos Hermenegildo,2,3 Federico V Pallardó,1â 3 José Luis GarcÃa-Giménez1â 3 1Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; 2Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain; 3Departamento de FisiologÃa, Facultad de Medicina y OdontologÃa, Universitat de València, València, SpainCorrespondence: José Luis GarcÃa-Giménez, Departamento de FisiologÃa, Facultad de Medicina y OdontologÃa, Universitat de València, València, 46010, Spain, Tel +34 963 864 646, Email j.luis.garcia@uv.esIntroduction: Circulating extracellular histones acquire relevance as cytotoxic mediators in sepsis. Extracellular histones act as damage-associated molecular patterns (DAMPs), which induce oxidative stress and NLRP3 inflammasome activation. Inflammasome mediates pyroptosis, a programmed cell death mechanism that produces inflammation. Despite evidence for inflammasome activation in immune cells during sepsis, it was unknown whether extracellular histones can produce endothelial inflammasomes activation.Methods: We used human umbilical vein endothelial cells (HUVEC) to explore the activation of pyroptosis, endothelial function and inflammation by extracellular histones. We evaluated pyroptosis by flow cytometry, caspase-1 activity assay, and gene and protein expression analysis by RT-qPCR and Western blot, respectively. The upstream molecular responses involved in pyroptosis activation by extracellular histones were validated by means of using antioxidant glutathione ethyl ester and NLRP3 inflammasome inhibitors. Finally, using mass spectrometry, we measured circulating histones in blood from critically-ill patients and demonstrated that circulating histone levels correlated with the expression of pyroptosis-related cytokines, the release of endothelial adhesion factors and septic shock severity.Results: We found that extracellular histones mediate the activation of NLRP3 inflammasome and pyroptosis in endothelial cells by contributing to endothelial dysfunction and the dysregulation of the immune response mediated by endothelium. Likewise, we demonstrated how the hyperacetylation of extracellular histones or the use of antioxidants decreased pyroptosis. In addition, we showed that pyroptosis is a feasible process occurring in septic shock patients.Discussion: Circulating histone levels correlated with the expression of pro-inflammatory and pyroptosis-related cytokines, the release of endothelial adhesion factors and septic shock severity. We propose to block histone-mediated pyroptosis as a feasible therapeutic strategy in sepsis.Graphical Abstract: Keywords: sepsis, extracellular histones, histone acetylation, endothelium, inflammasome, NLRP3 |
