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Chronically Elevated O-GlcNAcylation Limits Nitric Oxide Production and Deregulates Specific Pro-Inflammatory Cytokines

Inflammation is the immune response to harmful stimuli, including pathogens, damaged cells and toxic compounds. However, uncontrolled inflammation can be detrimental and contribute to numerous chronic inflammatory diseases, such as insulin resistance. At the forefront of this response are macrophage...

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Detalles Bibliográficos
Autores principales: Abramowitz, Lara K., Hanover, John A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010940/
https://www.ncbi.nlm.nih.gov/pubmed/35432339
http://dx.doi.org/10.3389/fimmu.2022.802336
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author Abramowitz, Lara K.
Hanover, John A.
author_facet Abramowitz, Lara K.
Hanover, John A.
author_sort Abramowitz, Lara K.
collection PubMed
description Inflammation is the immune response to harmful stimuli, including pathogens, damaged cells and toxic compounds. However, uncontrolled inflammation can be detrimental and contribute to numerous chronic inflammatory diseases, such as insulin resistance. At the forefront of this response are macrophages, which sense the local microenvironment to respond with a pro-inflammatory, M1-polarized phenotype, or anti-inflammatory, M2-polarized phenotype. M1 macrophages upregulate factors like pro-inflammatory cytokines, to promote inflammatory signaling, and inducible Nitric Oxide Synthase (iNOS), to produce nitric oxide (NO). The generated NO can kill microorganisms to protect the body, but also signal back to the macrophage to limit pro-inflammatory cytokine production to maintain macrophage homeostasis. Thus, the tight regulation of iNOS in macrophages is critical for the immune system. Here, we investigated how elevation of the nutrient-sensitive posttranslational modification, O-GlcNAc, impacts M1 polarized macrophages. We identified increased gene expression of specific pro-inflammatory cytokines (Il-6, Il-1β, Il-12) when O-GlcNAc cycling was blocked. We further uncovered an interaction between O-GlcNAc and iNOS, with iNOS being an OGT target in vitro. Analysis of M1 polarized bone marrow derived macrophages deficient in the enzyme that removes O-GlcNAc, O-GlcNAcase (OGA), revealed decreased iNOS activity as measured by a reduction in NO release. Further, elevated O-GlcNAc acted on Il-6 expression through the iNOS pathway, as iNOS inhibitior L-NIL raised wildtype Il-6 expression similar to OGA deficient cells but had no further effect on the hyper-O-GlcNAcylated cells. Thus O-GlcNAc contributes to macrophage homeostasis through modulation of iNOS activity.
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spelling pubmed-90109402022-04-16 Chronically Elevated O-GlcNAcylation Limits Nitric Oxide Production and Deregulates Specific Pro-Inflammatory Cytokines Abramowitz, Lara K. Hanover, John A. Front Immunol Immunology Inflammation is the immune response to harmful stimuli, including pathogens, damaged cells and toxic compounds. However, uncontrolled inflammation can be detrimental and contribute to numerous chronic inflammatory diseases, such as insulin resistance. At the forefront of this response are macrophages, which sense the local microenvironment to respond with a pro-inflammatory, M1-polarized phenotype, or anti-inflammatory, M2-polarized phenotype. M1 macrophages upregulate factors like pro-inflammatory cytokines, to promote inflammatory signaling, and inducible Nitric Oxide Synthase (iNOS), to produce nitric oxide (NO). The generated NO can kill microorganisms to protect the body, but also signal back to the macrophage to limit pro-inflammatory cytokine production to maintain macrophage homeostasis. Thus, the tight regulation of iNOS in macrophages is critical for the immune system. Here, we investigated how elevation of the nutrient-sensitive posttranslational modification, O-GlcNAc, impacts M1 polarized macrophages. We identified increased gene expression of specific pro-inflammatory cytokines (Il-6, Il-1β, Il-12) when O-GlcNAc cycling was blocked. We further uncovered an interaction between O-GlcNAc and iNOS, with iNOS being an OGT target in vitro. Analysis of M1 polarized bone marrow derived macrophages deficient in the enzyme that removes O-GlcNAc, O-GlcNAcase (OGA), revealed decreased iNOS activity as measured by a reduction in NO release. Further, elevated O-GlcNAc acted on Il-6 expression through the iNOS pathway, as iNOS inhibitior L-NIL raised wildtype Il-6 expression similar to OGA deficient cells but had no further effect on the hyper-O-GlcNAcylated cells. Thus O-GlcNAc contributes to macrophage homeostasis through modulation of iNOS activity. Frontiers Media S.A. 2022-04-01 /pmc/articles/PMC9010940/ /pubmed/35432339 http://dx.doi.org/10.3389/fimmu.2022.802336 Text en Copyright © 2022 Abramowitz and Hanover https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Abramowitz, Lara K.
Hanover, John A.
Chronically Elevated O-GlcNAcylation Limits Nitric Oxide Production and Deregulates Specific Pro-Inflammatory Cytokines
title Chronically Elevated O-GlcNAcylation Limits Nitric Oxide Production and Deregulates Specific Pro-Inflammatory Cytokines
title_full Chronically Elevated O-GlcNAcylation Limits Nitric Oxide Production and Deregulates Specific Pro-Inflammatory Cytokines
title_fullStr Chronically Elevated O-GlcNAcylation Limits Nitric Oxide Production and Deregulates Specific Pro-Inflammatory Cytokines
title_full_unstemmed Chronically Elevated O-GlcNAcylation Limits Nitric Oxide Production and Deregulates Specific Pro-Inflammatory Cytokines
title_short Chronically Elevated O-GlcNAcylation Limits Nitric Oxide Production and Deregulates Specific Pro-Inflammatory Cytokines
title_sort chronically elevated o-glcnacylation limits nitric oxide production and deregulates specific pro-inflammatory cytokines
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010940/
https://www.ncbi.nlm.nih.gov/pubmed/35432339
http://dx.doi.org/10.3389/fimmu.2022.802336
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