Extracellular Lactate Acts as a Metabolic Checkpoint and Shapes Monocyte Function Time Dependently

Elevated blood lactate levels are frequently found in critically ill patients and thought to result from tissue hypoperfusion and cellular oxygen shortage. Considering the close relationship between immune cell function and intracellular metabolism, lactate is more than a glycolytic waste molecule b...

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Autores principales:	Judith Schenz, Lena Heilig, Tim Lohse, Lucas Tichy, Katharina Bomans, Michael Büttner, Markus A. Weigand, Florian Uhle
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	critically ill glycolysis immunometabolism polyol pathway sepsis sorbitol Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/fc60e8d7faaa4f3fafc88866019d4f2a
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spelling	oai:doaj.org-article:fc60e8d7faaa4f3fafc88866019d4f2a2021-11-30T18:27:43ZExtracellular Lactate Acts as a Metabolic Checkpoint and Shapes Monocyte Function Time Dependently1664-322410.3389/fimmu.2021.729209https://doaj.org/article/fc60e8d7faaa4f3fafc88866019d4f2a2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.729209/fullhttps://doaj.org/toc/1664-3224Elevated blood lactate levels are frequently found in critically ill patients and thought to result from tissue hypoperfusion and cellular oxygen shortage. Considering the close relationship between immune cell function and intracellular metabolism, lactate is more than a glycolytic waste molecule but able to regulate the immune response. Our aim was to elucidate the temporal and mechanistic effect of extracellular lactate on monocytes. To this end, primary human monocytes and the human monocytic cell line MonoMac6 were stimulated with various toll-like-receptor agonists after priming with Na-L-lactate under constant pH conditions. As readout, cytokine production was measured, real-time assessment of intracellular energy pathways was performed, and intracellular metabolite concentrations were determined. Irrespective of the immunogenic stimulus, short-term Na-lactate-priming strongly reduced cytokine production capacity. Lactate and hexoses accumulated intracellularly and, together with a decreased glycolytic flux, indicate a lactate-triggered impairment of glycolysis. To counteract intracellular hyperglycemia, glucose is shunted into the branching polyol pathway, leading to sorbitol accumulation. In contrast, long-term priming with Na-L-lactate induced cellular adaption and abolished the suppressive effect. This lactate tolerance is characterized by a decreased cellular respiration due to a reduced complex-I activity. Our results indicate that exogenous lactate shapes monocyte function by altering the intracellular energy metabolism and acts as a metabolic checkpoint of monocyte activation.Judith SchenzLena HeiligTim LohseLucas TichyKatharina BomansMichael BüttnerMarkus A. WeigandFlorian UhleFrontiers Media S.A.articlecritically illglycolysisimmunometabolismpolyol pathwaysepsissorbitolImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	critically ill glycolysis immunometabolism polyol pathway sepsis sorbitol Immunologic diseases. Allergy RC581-607
spellingShingle	critically ill glycolysis immunometabolism polyol pathway sepsis sorbitol Immunologic diseases. Allergy RC581-607 Judith Schenz Lena Heilig Tim Lohse Lucas Tichy Katharina Bomans Michael Büttner Markus A. Weigand Florian Uhle Extracellular Lactate Acts as a Metabolic Checkpoint and Shapes Monocyte Function Time Dependently
description	Elevated blood lactate levels are frequently found in critically ill patients and thought to result from tissue hypoperfusion and cellular oxygen shortage. Considering the close relationship between immune cell function and intracellular metabolism, lactate is more than a glycolytic waste molecule but able to regulate the immune response. Our aim was to elucidate the temporal and mechanistic effect of extracellular lactate on monocytes. To this end, primary human monocytes and the human monocytic cell line MonoMac6 were stimulated with various toll-like-receptor agonists after priming with Na-L-lactate under constant pH conditions. As readout, cytokine production was measured, real-time assessment of intracellular energy pathways was performed, and intracellular metabolite concentrations were determined. Irrespective of the immunogenic stimulus, short-term Na-lactate-priming strongly reduced cytokine production capacity. Lactate and hexoses accumulated intracellularly and, together with a decreased glycolytic flux, indicate a lactate-triggered impairment of glycolysis. To counteract intracellular hyperglycemia, glucose is shunted into the branching polyol pathway, leading to sorbitol accumulation. In contrast, long-term priming with Na-L-lactate induced cellular adaption and abolished the suppressive effect. This lactate tolerance is characterized by a decreased cellular respiration due to a reduced complex-I activity. Our results indicate that exogenous lactate shapes monocyte function by altering the intracellular energy metabolism and acts as a metabolic checkpoint of monocyte activation.
format	article
author	Judith Schenz Lena Heilig Tim Lohse Lucas Tichy Katharina Bomans Michael Büttner Markus A. Weigand Florian Uhle
author_facet	Judith Schenz Lena Heilig Tim Lohse Lucas Tichy Katharina Bomans Michael Büttner Markus A. Weigand Florian Uhle
author_sort	Judith Schenz
title	Extracellular Lactate Acts as a Metabolic Checkpoint and Shapes Monocyte Function Time Dependently
title_short	Extracellular Lactate Acts as a Metabolic Checkpoint and Shapes Monocyte Function Time Dependently
title_full	Extracellular Lactate Acts as a Metabolic Checkpoint and Shapes Monocyte Function Time Dependently
title_fullStr	Extracellular Lactate Acts as a Metabolic Checkpoint and Shapes Monocyte Function Time Dependently
title_full_unstemmed	Extracellular Lactate Acts as a Metabolic Checkpoint and Shapes Monocyte Function Time Dependently
title_sort	extracellular lactate acts as a metabolic checkpoint and shapes monocyte function time dependently
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/fc60e8d7faaa4f3fafc88866019d4f2a
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Extracellular Lactate Acts as a Metabolic Checkpoint and Shapes Monocyte Function Time Dependently

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