JAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis

Microbial challenges, such as widespread bacterial infection in sepsis, induce endotoxin tolerance, a state of hyporesponsiveness to subsequent infections. The participation of DNA methylation in this process is poorly known. In this study, we perform integrated analysis of DNA methylation and trans...

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Autores principales:	Octavio Morante-Palacios, Clara Lorente-Sorolla, Laura Ciudad, Josep Calafell-Segura, Antonio Garcia-Gomez, Francesc Català-Moll, Adolfo Ruiz-Sanmartín, Mónica Martínez-Gallo, Ricard Ferrer, Juan Carlos Ruiz-Rodriguez, Damiana Álvarez-Errico, Esteban Ballestar
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	monocytes endotoxin tolerance sepsis DNA methylation tolerized genes STATs Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/49184cea2fcd4e56b292273927f9285f
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spelling	oai:doaj.org-article:49184cea2fcd4e56b292273927f9285f2021-11-17T06:43:23ZJAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis1664-322410.3389/fimmu.2021.734652https://doaj.org/article/49184cea2fcd4e56b292273927f9285f2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.734652/fullhttps://doaj.org/toc/1664-3224Microbial challenges, such as widespread bacterial infection in sepsis, induce endotoxin tolerance, a state of hyporesponsiveness to subsequent infections. The participation of DNA methylation in this process is poorly known. In this study, we perform integrated analysis of DNA methylation and transcriptional changes following in vitro exposure to gram-negative bacterial lipopolysaccharide, together with analysis of ex vivo monocytes from septic patients. We identify TET2-mediated demethylation and transcriptional activation of inflammation-related genes that is specific to toll-like receptor stimulation. Changes also involve phosphorylation of STAT1, STAT3 and STAT5, elements of the JAK2 pathway. JAK2 pathway inhibition impairs the activation of tolerized genes on the first encounter with lipopolysaccharide. We then confirm the implication of the JAK2-STAT pathway in the aberrant DNA methylome of patients with sepsis caused by gram-negative bacteria. Finally, JAK2 inhibition in monocytes partially recapitulates the expression changes produced in the immunosuppressive cellular state acquired by monocytes from gram-negative sepsis, as described by single cell-RNA-sequencing. Our study evidences both the crucial role the JAK2-STAT pathway in epigenetic regulation and initial response of the tolerized genes to gram-negative bacterial endotoxins and provides a pharmacological target to prevent exacerbated responses.Octavio Morante-PalaciosClara Lorente-SorollaLaura CiudadJosep Calafell-SeguraAntonio Garcia-GomezFrancesc Català-MollAdolfo Ruiz-SanmartínMónica Martínez-GalloRicard FerrerJuan Carlos Ruiz-RodriguezDamiana Álvarez-ErricoEsteban BallestarFrontiers Media S.A.articlemonocytesendotoxin tolerancesepsisDNA methylationtolerized genesSTATsImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	monocytes endotoxin tolerance sepsis DNA methylation tolerized genes STATs Immunologic diseases. Allergy RC581-607
spellingShingle	monocytes endotoxin tolerance sepsis DNA methylation tolerized genes STATs Immunologic diseases. Allergy RC581-607 Octavio Morante-Palacios Clara Lorente-Sorolla Laura Ciudad Josep Calafell-Segura Antonio Garcia-Gomez Francesc Català-Moll Adolfo Ruiz-Sanmartín Mónica Martínez-Gallo Ricard Ferrer Juan Carlos Ruiz-Rodriguez Damiana Álvarez-Errico Esteban Ballestar JAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis
description	Microbial challenges, such as widespread bacterial infection in sepsis, induce endotoxin tolerance, a state of hyporesponsiveness to subsequent infections. The participation of DNA methylation in this process is poorly known. In this study, we perform integrated analysis of DNA methylation and transcriptional changes following in vitro exposure to gram-negative bacterial lipopolysaccharide, together with analysis of ex vivo monocytes from septic patients. We identify TET2-mediated demethylation and transcriptional activation of inflammation-related genes that is specific to toll-like receptor stimulation. Changes also involve phosphorylation of STAT1, STAT3 and STAT5, elements of the JAK2 pathway. JAK2 pathway inhibition impairs the activation of tolerized genes on the first encounter with lipopolysaccharide. We then confirm the implication of the JAK2-STAT pathway in the aberrant DNA methylome of patients with sepsis caused by gram-negative bacteria. Finally, JAK2 inhibition in monocytes partially recapitulates the expression changes produced in the immunosuppressive cellular state acquired by monocytes from gram-negative sepsis, as described by single cell-RNA-sequencing. Our study evidences both the crucial role the JAK2-STAT pathway in epigenetic regulation and initial response of the tolerized genes to gram-negative bacterial endotoxins and provides a pharmacological target to prevent exacerbated responses.
format	article
author	Octavio Morante-Palacios Clara Lorente-Sorolla Laura Ciudad Josep Calafell-Segura Antonio Garcia-Gomez Francesc Català-Moll Adolfo Ruiz-Sanmartín Mónica Martínez-Gallo Ricard Ferrer Juan Carlos Ruiz-Rodriguez Damiana Álvarez-Errico Esteban Ballestar
author_facet	Octavio Morante-Palacios Clara Lorente-Sorolla Laura Ciudad Josep Calafell-Segura Antonio Garcia-Gomez Francesc Català-Moll Adolfo Ruiz-Sanmartín Mónica Martínez-Gallo Ricard Ferrer Juan Carlos Ruiz-Rodriguez Damiana Álvarez-Errico Esteban Ballestar
author_sort	Octavio Morante-Palacios
title	JAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis
title_short	JAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis
title_full	JAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis
title_fullStr	JAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis
title_full_unstemmed	JAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis
title_sort	jak2-stat epigenetically regulates tolerized genes in monocytes in the first encounter with gram-negative bacterial endotoxins in sepsis
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/49184cea2fcd4e56b292273927f9285f
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JAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis

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