TY - JOUR
T1 - Inflammatory cytokines and organ dysfunction associate with the aberrant DNA methylome of monocytes in sepsis
AU - Lorente-Sorolla, Clara
AU - Garcia-Gomez, Antonio
AU - Català-Moll, Francesc
AU - Toledano, Víctor
AU - Ciudad, Laura
AU - Avendaño-Ortiz, José
AU - Maroun-Eid, Charbel
AU - Martín-Quirós, Alejandro
AU - Martínez-Gallo, Mónica
AU - Ruiz-Sanmartín, Adolfo
AU - Del Campo, Álvaro García
AU - Ferrer-Roca, Ricard
AU - Ruiz-Rodriguez, Juan Carlos
AU - Álvarez-Errico, Damiana
AU - López-Collazo, Eduardo
AU - Ballestar, Esteban
N1 - Publisher Copyright:
© 2019 The Author(s).
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/10/29
Y1 - 2019/10/29
N2 - 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, non-infectious 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.
AB - 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, non-infectious 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.
KW - Cytokines
KW - DNA methylation
KW - Endotoxin tolerance
KW - Monocytes
KW - Sepsis
UR - http://www.scopus.com/inward/record.url?scp=85074356877&partnerID=8YFLogxK
U2 - 10.1186/s13073-019-0674-2
DO - 10.1186/s13073-019-0674-2
M3 - Article
C2 - 31665078
AN - SCOPUS:85074356877
SN - 1756-994X
VL - 11
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 66
ER -