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The Effect of Rev-erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia

Microglia are the immune cells of the brain. Hyperactivation of microglia contributes to the pathology of metabolic and neuroinflammatory diseases. Evidence has emerged that links the circadian clock, cellular metabolism, and immune activity in microglia. Rev-erb nuclear receptors are known for thei...

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Autores principales: Wolff, Samantha E. C., Wang, Xiao-Lan, Jiao, Han, Sun, Jia, Kalsbeek, Andries, Yi, Chun-Xia, Gao, Yuanqing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546349/
https://www.ncbi.nlm.nih.gov/pubmed/33101272
http://dx.doi.org/10.3389/fimmu.2020.550145
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author Wolff, Samantha E. C.
Wang, Xiao-Lan
Jiao, Han
Sun, Jia
Kalsbeek, Andries
Yi, Chun-Xia
Gao, Yuanqing
author_facet Wolff, Samantha E. C.
Wang, Xiao-Lan
Jiao, Han
Sun, Jia
Kalsbeek, Andries
Yi, Chun-Xia
Gao, Yuanqing
author_sort Wolff, Samantha E. C.
collection PubMed
description Microglia are the immune cells of the brain. Hyperactivation of microglia contributes to the pathology of metabolic and neuroinflammatory diseases. Evidence has emerged that links the circadian clock, cellular metabolism, and immune activity in microglia. Rev-erb nuclear receptors are known for their regulatory role in both the molecular clock and cell metabolism, and have recently been found to play an important role in neuroinflammation. The Rev-erbα agonist SR9011 disrupts circadian rhythm by altering intracellular clock machinery. However, the exact role of Rev-erbα in microglial immunometabolism remains to be elucidated. In the current study, we explored whether SR9011 also had such a detrimental impact on microglial immunometabolic functions. Primary microglia were isolated from 1–3 days old Sprague-Dawley rat pups. The expression of clock genes, cytokines and metabolic genes was evaluated using RT-PCR and rhythmic expression was analyzed. Phagocytic activity was determined by the uptake capacity of fluorescent microspheres. Mitochondria function was evaluated by measuring oxygen consumption rate and extracellular acidification rate. We found that key cytokines and metabolic genes are rhythmically expressed in microglia. SR9011 disturbed rhythmic expression of clock genes in microglia. Pro-inflammatory cytokine expression was attenuated by SR9011 during an immune challenge by TNFα, while expression of the anti-inflammatory cytokine Il10 was stimulated. Moreover, SR9011 decreased phagocytic activity, mitochondrial respiration, ATP production, and metabolic gene expression. Our study highlights the link between the intrinsic clock and immunometabolism of microglia. We show that Rev-erbα is implicated in both metabolic homeostasis and the inflammatory responses in microglia, which has important implications for the treatment of metabolic and neuroinflammatory diseases.
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spelling pubmed-75463492020-10-22 The Effect of Rev-erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia Wolff, Samantha E. C. Wang, Xiao-Lan Jiao, Han Sun, Jia Kalsbeek, Andries Yi, Chun-Xia Gao, Yuanqing Front Immunol Immunology Microglia are the immune cells of the brain. Hyperactivation of microglia contributes to the pathology of metabolic and neuroinflammatory diseases. Evidence has emerged that links the circadian clock, cellular metabolism, and immune activity in microglia. Rev-erb nuclear receptors are known for their regulatory role in both the molecular clock and cell metabolism, and have recently been found to play an important role in neuroinflammation. The Rev-erbα agonist SR9011 disrupts circadian rhythm by altering intracellular clock machinery. However, the exact role of Rev-erbα in microglial immunometabolism remains to be elucidated. In the current study, we explored whether SR9011 also had such a detrimental impact on microglial immunometabolic functions. Primary microglia were isolated from 1–3 days old Sprague-Dawley rat pups. The expression of clock genes, cytokines and metabolic genes was evaluated using RT-PCR and rhythmic expression was analyzed. Phagocytic activity was determined by the uptake capacity of fluorescent microspheres. Mitochondria function was evaluated by measuring oxygen consumption rate and extracellular acidification rate. We found that key cytokines and metabolic genes are rhythmically expressed in microglia. SR9011 disturbed rhythmic expression of clock genes in microglia. Pro-inflammatory cytokine expression was attenuated by SR9011 during an immune challenge by TNFα, while expression of the anti-inflammatory cytokine Il10 was stimulated. Moreover, SR9011 decreased phagocytic activity, mitochondrial respiration, ATP production, and metabolic gene expression. Our study highlights the link between the intrinsic clock and immunometabolism of microglia. We show that Rev-erbα is implicated in both metabolic homeostasis and the inflammatory responses in microglia, which has important implications for the treatment of metabolic and neuroinflammatory diseases. Frontiers Media S.A. 2020-09-25 /pmc/articles/PMC7546349/ /pubmed/33101272 http://dx.doi.org/10.3389/fimmu.2020.550145 Text en Copyright © 2020 Wolff, Wang, Jiao, Sun, Kalsbeek, Yi and Gao. http://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
Wolff, Samantha E. C.
Wang, Xiao-Lan
Jiao, Han
Sun, Jia
Kalsbeek, Andries
Yi, Chun-Xia
Gao, Yuanqing
The Effect of Rev-erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia
title The Effect of Rev-erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia
title_full The Effect of Rev-erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia
title_fullStr The Effect of Rev-erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia
title_full_unstemmed The Effect of Rev-erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia
title_short The Effect of Rev-erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia
title_sort effect of rev-erbα agonist sr9011 on the immune response and cell metabolism of microglia
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546349/
https://www.ncbi.nlm.nih.gov/pubmed/33101272
http://dx.doi.org/10.3389/fimmu.2020.550145
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