Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan

(1→3)-β-D-Glucan (BDG) represents a potent pathogen-associated molecular pattern (PAMP) in triggering the host response to fungal and some bacterial infections. Monocytes play a key role in recognizing BDG and governing the acute host response to infections. However, the mechanisms regulating monocy...

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Autores principales:	Rayoun Ramendra, Mathieu Mancini, Jose-Mauricio Ayala, Lin Tze Tung, Stephane Isnard, John Lin, Jean-Pierre Routy, Anastasia Nijnik, David Langlais
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	B-glucan glutathione immunometabolism innate immunity host response Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/254699ac6a0b42219bb8f73ee1c5c702
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spelling	oai:doaj.org-article:254699ac6a0b42219bb8f73ee1c5c7022021-11-11T05:10:23ZGlutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan1664-322410.3389/fimmu.2021.694152https://doaj.org/article/254699ac6a0b42219bb8f73ee1c5c7022021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.694152/fullhttps://doaj.org/toc/1664-3224(1→3)-β-D-Glucan (BDG) represents a potent pathogen-associated molecular pattern (PAMP) in triggering the host response to fungal and some bacterial infections. Monocytes play a key role in recognizing BDG and governing the acute host response to infections. However, the mechanisms regulating monocyte’s acute response to BDG are poorly understood. We sought to investigate the response of monocytes to BDG at the epigenetic, transcriptomic, and molecular levels. Response of human monocytes to 1, 4, and 24 hours of BDG exposure was investigated using RNA-seq, ATAC-seq, H3K27ac and H3K4me1 ChIP-seq. We show that pathways including glutathione metabolism, pentose phosphate pathway, and citric acid cycle were upregulated at the epigenetic and transcriptomic levels in response to BDG exposure. Strikingly, unlike bacterial lipopolysaccharides, BDG induced intracellular glutathione synthesis. BDG exposure also induced NADP synthesis, increased NADPH/NADP ratio, and increased expression of genes involved in the pentose phosphate pathway in a GSH-dependent manner. By inhibiting GSH synthesis with L-buthionine sulfoximine (BSO) before BDG exposure we show that the GSH pathway promotes cell survival and regulates monocyte’s effector functions including NO production, phagocytosis, and cytokine production. In summary, our work demonstrates that BDG induces glutathione synthesis and metabolism in monocytes, which is a major promoter of the acute functional response of monocytes to infections.Rayoun RamendraRayoun RamendraRayoun RamendraMathieu ManciniMathieu ManciniMathieu ManciniJose-Mauricio AyalaJose-Mauricio AyalaJose-Mauricio AyalaLin Tze TungLin Tze TungStephane IsnardJohn LinJean-Pierre RoutyAnastasia NijnikAnastasia NijnikDavid LanglaisDavid LanglaisDavid LanglaisDavid LanglaisFrontiers Media S.A.articleB-glucanglutathioneimmunometabolisminnate immunityhost responseImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	B-glucan glutathione immunometabolism innate immunity host response Immunologic diseases. Allergy RC581-607
spellingShingle	B-glucan glutathione immunometabolism innate immunity host response Immunologic diseases. Allergy RC581-607 Rayoun Ramendra Rayoun Ramendra Rayoun Ramendra Mathieu Mancini Mathieu Mancini Mathieu Mancini Jose-Mauricio Ayala Jose-Mauricio Ayala Jose-Mauricio Ayala Lin Tze Tung Lin Tze Tung Stephane Isnard John Lin Jean-Pierre Routy Anastasia Nijnik Anastasia Nijnik David Langlais David Langlais David Langlais David Langlais Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan
description	(1→3)-β-D-Glucan (BDG) represents a potent pathogen-associated molecular pattern (PAMP) in triggering the host response to fungal and some bacterial infections. Monocytes play a key role in recognizing BDG and governing the acute host response to infections. However, the mechanisms regulating monocyte’s acute response to BDG are poorly understood. We sought to investigate the response of monocytes to BDG at the epigenetic, transcriptomic, and molecular levels. Response of human monocytes to 1, 4, and 24 hours of BDG exposure was investigated using RNA-seq, ATAC-seq, H3K27ac and H3K4me1 ChIP-seq. We show that pathways including glutathione metabolism, pentose phosphate pathway, and citric acid cycle were upregulated at the epigenetic and transcriptomic levels in response to BDG exposure. Strikingly, unlike bacterial lipopolysaccharides, BDG induced intracellular glutathione synthesis. BDG exposure also induced NADP synthesis, increased NADPH/NADP ratio, and increased expression of genes involved in the pentose phosphate pathway in a GSH-dependent manner. By inhibiting GSH synthesis with L-buthionine sulfoximine (BSO) before BDG exposure we show that the GSH pathway promotes cell survival and regulates monocyte’s effector functions including NO production, phagocytosis, and cytokine production. In summary, our work demonstrates that BDG induces glutathione synthesis and metabolism in monocytes, which is a major promoter of the acute functional response of monocytes to infections.
format	article
author	Rayoun Ramendra Rayoun Ramendra Rayoun Ramendra Mathieu Mancini Mathieu Mancini Mathieu Mancini Jose-Mauricio Ayala Jose-Mauricio Ayala Jose-Mauricio Ayala Lin Tze Tung Lin Tze Tung Stephane Isnard John Lin Jean-Pierre Routy Anastasia Nijnik Anastasia Nijnik David Langlais David Langlais David Langlais David Langlais
author_facet	Rayoun Ramendra Rayoun Ramendra Rayoun Ramendra Mathieu Mancini Mathieu Mancini Mathieu Mancini Jose-Mauricio Ayala Jose-Mauricio Ayala Jose-Mauricio Ayala Lin Tze Tung Lin Tze Tung Stephane Isnard John Lin Jean-Pierre Routy Anastasia Nijnik Anastasia Nijnik David Langlais David Langlais David Langlais David Langlais
author_sort	Rayoun Ramendra
title	Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan
title_short	Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan
title_full	Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan
title_fullStr	Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan
title_full_unstemmed	Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan
title_sort	glutathione metabolism is a regulator of the acute inflammatory response of monocytes to (1→3)-β-d-glucan
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/254699ac6a0b42219bb8f73ee1c5c702
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Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan

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