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Title: Inflammatory cytokines and organ dysfunction associate with the aberrant DNA methylome of monocytes in sepsis
Author: Lorente-Sorolla Martínez-Acítores, Clara
García Gómez, Antonio
Català Moll, Francesc
Toledano, Víctor
Ciudad, Laura
Avendano Ortiz, José
Maroun-Eid, Charbel
Martín Quirós, Alejandro
Martínez Gallo, Mónica
Ruiz Sanmartín, Adolfo
García del Campo, Álvaro
Ferrer Roca, Ricard
Ruiz Rodríguez, Juan Carlos
Álvarez Errico, Damiana
López Collazo, Eduardo
Ballestar Tarín, Esteban
Keywords: Insuficiència respiratòria
Respiratory insufficiency
Issue Date: 29-Oct-2019
Publisher: BioMed Central
Abstract: Background: Sepsis, a life-threatening organ dysfunction caused by a dysregulated systemic immune response to infection, associates with reduced responsiveness to subsequent infections. How such tolerance is acquired is not well understood but is known to involve epigenetic and transcriptional dysregulation. Methods: Bead arrays were used to compare global DNA methylation changes in patients with sepsis, noninfectious systemic inflammatory response syndrome, and healthy controls. Bioinformatic analyses were performed to dissect functional reprogramming and signaling pathways related to the acquisition of these specific DNA methylation alterations. Finally, in vitro experiments using human monocytes were performed to test the induction of similar DNA methylation reprogramming. Results: Here, we focused on DNA methylation changes associated with sepsis, given their potential role in stabilizing altered phenotypes. Tolerized monocytes from patients with sepsis display changes in their DNA methylomes with respect to those from healthy controls, affecting critical monocyte-related genes. DNA methylation profiles correlate with IL-10 and IL-6 levels, significantly increased in monocytes in sepsis, as well as with the Sequential Organ Failure Assessment score; the observed changes associate with TFs and pathways downstream to toll-like receptors and inflammatory cytokines. In fact, in vitro stimulation of toll-like receptors in monocytes results in similar gains and losses of methylation together with the acquisition of tolerance. Conclusion: We have identified a DNA methylation signature associated with sepsis that is downstream to the response of monocytes to inflammatory signals associated with the acquisition of a tolerized phenotype and organic dysfunction.
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It is part of: Genome Medicine, 2019-10-29, vol. 11
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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