The intrinsic microglial clock system regulates interleukin-6 expression

Ryota Nakazato, Shogo Hotta, Daisuke Yamada, Miki Kou, Saki Nakamura, Yoshifumi Takahata, Hajime Tei, Rika Numano, Akiko Hida, Shigeki Shimba, Michihiro Mieda, Eiichi Hinoi, Yukio Yoneda, Takeshi Takarada

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Similar to neurons, microglia have an intrinsic molecular clock. The master clock oscillator Bmal1 modulates interleukin-6 upregulation in microglial cells exposed to lipopolysaccharide. Bmal1 can play a role in microglial inflammatory responses. We previously demonstrated that gliotransmitter ATP induces transient expression of the clock gene Period1 via P2X7 purinergic receptors in cultured microglia. In this study, we further investigated mechanisms underlying the regulation of pro-inflammatory cytokine production by clock molecules in microglial cells. Several clock gene transcripts exhibited oscillatory diurnal rhythmicity in microglial BV-2 cells. Real-time luciferase monitoring also showed diurnal oscillatory luciferase activity in cultured microglia from Per1::Luciferase transgenic mice. Lipopolysaccharide (LPS) strongly induced the expression of pro-inflammatory cytokines in BV-2 cells, whereas an siRNA targeting Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), a core positive component of the microglial molecular clock, selectively inhibited LPS-induced interleukin-6 (IL-6) expression. In addition, LPS-induced IL-6 expression was attenuated in microglia from Bmal1-deficient mice. This phenotype was recapitulated by pharmacological disruption of oscillatory diurnal rhythmicity using the synthetic Rev-Erb agonist SR9011. Promoter analysis of the Il6 gene revealed that Bmal1 is required for LPS-induced IL-6 expression in microglia. Mice conditionally Bmal1 deficient in cells expressing CD11b, including microglia, exhibited less potent upregulation of Il6 expression following middle cerebral artery occlusion compared with that in control mice, with a significant attenuation of neuronal damage. These results suggest that the intrinsic microglial clock modulates the inflammatory response, including the positive regulation of IL-6 expression in a particular pathological situation in the brain, GLIA 2016. GLIA 2017;65:198–208.

Original languageEnglish
Pages (from-to)198-208
Number of pages11
JournalGLIA
Volume65
Issue number1
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

Microglia
Interleukin-6
Lipopolysaccharides
Luciferases
Periodicity
ARNTL Transcription Factors
Up-Regulation
Purinergic P2X7 Receptors
Cytokines
Middle Cerebral Artery Infarction
Brain
Small Interfering RNA
Transgenic Mice
Genes
Adenosine Triphosphate
Pharmacology
Phenotype
Gene Expression
Neurons
Muscles

Keywords

  • Bmal1
  • clock genes
  • IL-6
  • microglia

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

The intrinsic microglial clock system regulates interleukin-6 expression. / Nakazato, Ryota; Hotta, Shogo; Yamada, Daisuke; Kou, Miki; Nakamura, Saki; Takahata, Yoshifumi; Tei, Hajime; Numano, Rika; Hida, Akiko; Shimba, Shigeki; Mieda, Michihiro; Hinoi, Eiichi; Yoneda, Yukio; Takarada, Takeshi.

In: GLIA, Vol. 65, No. 1, 01.01.2017, p. 198-208.

Research output: Contribution to journalArticle

Nakazato, R, Hotta, S, Yamada, D, Kou, M, Nakamura, S, Takahata, Y, Tei, H, Numano, R, Hida, A, Shimba, S, Mieda, M, Hinoi, E, Yoneda, Y & Takarada, T 2017, 'The intrinsic microglial clock system regulates interleukin-6 expression', GLIA, vol. 65, no. 1, pp. 198-208. https://doi.org/10.1002/glia.23087
Nakazato R, Hotta S, Yamada D, Kou M, Nakamura S, Takahata Y et al. The intrinsic microglial clock system regulates interleukin-6 expression. GLIA. 2017 Jan 1;65(1):198-208. https://doi.org/10.1002/glia.23087
Nakazato, Ryota ; Hotta, Shogo ; Yamada, Daisuke ; Kou, Miki ; Nakamura, Saki ; Takahata, Yoshifumi ; Tei, Hajime ; Numano, Rika ; Hida, Akiko ; Shimba, Shigeki ; Mieda, Michihiro ; Hinoi, Eiichi ; Yoneda, Yukio ; Takarada, Takeshi. / The intrinsic microglial clock system regulates interleukin-6 expression. In: GLIA. 2017 ; Vol. 65, No. 1. pp. 198-208.
@article{268f533959a54c74bd03da12670689fd,
title = "The intrinsic microglial clock system regulates interleukin-6 expression",
abstract = "Similar to neurons, microglia have an intrinsic molecular clock. The master clock oscillator Bmal1 modulates interleukin-6 upregulation in microglial cells exposed to lipopolysaccharide. Bmal1 can play a role in microglial inflammatory responses. We previously demonstrated that gliotransmitter ATP induces transient expression of the clock gene Period1 via P2X7 purinergic receptors in cultured microglia. In this study, we further investigated mechanisms underlying the regulation of pro-inflammatory cytokine production by clock molecules in microglial cells. Several clock gene transcripts exhibited oscillatory diurnal rhythmicity in microglial BV-2 cells. Real-time luciferase monitoring also showed diurnal oscillatory luciferase activity in cultured microglia from Per1::Luciferase transgenic mice. Lipopolysaccharide (LPS) strongly induced the expression of pro-inflammatory cytokines in BV-2 cells, whereas an siRNA targeting Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), a core positive component of the microglial molecular clock, selectively inhibited LPS-induced interleukin-6 (IL-6) expression. In addition, LPS-induced IL-6 expression was attenuated in microglia from Bmal1-deficient mice. This phenotype was recapitulated by pharmacological disruption of oscillatory diurnal rhythmicity using the synthetic Rev-Erb agonist SR9011. Promoter analysis of the Il6 gene revealed that Bmal1 is required for LPS-induced IL-6 expression in microglia. Mice conditionally Bmal1 deficient in cells expressing CD11b, including microglia, exhibited less potent upregulation of Il6 expression following middle cerebral artery occlusion compared with that in control mice, with a significant attenuation of neuronal damage. These results suggest that the intrinsic microglial clock modulates the inflammatory response, including the positive regulation of IL-6 expression in a particular pathological situation in the brain, GLIA 2016. GLIA 2017;65:198–208.",
keywords = "Bmal1, clock genes, IL-6, microglia",
author = "Ryota Nakazato and Shogo Hotta and Daisuke Yamada and Miki Kou and Saki Nakamura and Yoshifumi Takahata and Hajime Tei and Rika Numano and Akiko Hida and Shigeki Shimba and Michihiro Mieda and Eiichi Hinoi and Yukio Yoneda and Takeshi Takarada",
year = "2017",
month = "1",
day = "1",
doi = "10.1002/glia.23087",
language = "English",
volume = "65",
pages = "198--208",
journal = "GLIA",
issn = "0894-1491",
publisher = "John Wiley and Sons Inc.",
number = "1",

}

TY - JOUR

T1 - The intrinsic microglial clock system regulates interleukin-6 expression

AU - Nakazato, Ryota

AU - Hotta, Shogo

AU - Yamada, Daisuke

AU - Kou, Miki

AU - Nakamura, Saki

AU - Takahata, Yoshifumi

AU - Tei, Hajime

AU - Numano, Rika

AU - Hida, Akiko

AU - Shimba, Shigeki

AU - Mieda, Michihiro

AU - Hinoi, Eiichi

AU - Yoneda, Yukio

AU - Takarada, Takeshi

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Similar to neurons, microglia have an intrinsic molecular clock. The master clock oscillator Bmal1 modulates interleukin-6 upregulation in microglial cells exposed to lipopolysaccharide. Bmal1 can play a role in microglial inflammatory responses. We previously demonstrated that gliotransmitter ATP induces transient expression of the clock gene Period1 via P2X7 purinergic receptors in cultured microglia. In this study, we further investigated mechanisms underlying the regulation of pro-inflammatory cytokine production by clock molecules in microglial cells. Several clock gene transcripts exhibited oscillatory diurnal rhythmicity in microglial BV-2 cells. Real-time luciferase monitoring also showed diurnal oscillatory luciferase activity in cultured microglia from Per1::Luciferase transgenic mice. Lipopolysaccharide (LPS) strongly induced the expression of pro-inflammatory cytokines in BV-2 cells, whereas an siRNA targeting Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), a core positive component of the microglial molecular clock, selectively inhibited LPS-induced interleukin-6 (IL-6) expression. In addition, LPS-induced IL-6 expression was attenuated in microglia from Bmal1-deficient mice. This phenotype was recapitulated by pharmacological disruption of oscillatory diurnal rhythmicity using the synthetic Rev-Erb agonist SR9011. Promoter analysis of the Il6 gene revealed that Bmal1 is required for LPS-induced IL-6 expression in microglia. Mice conditionally Bmal1 deficient in cells expressing CD11b, including microglia, exhibited less potent upregulation of Il6 expression following middle cerebral artery occlusion compared with that in control mice, with a significant attenuation of neuronal damage. These results suggest that the intrinsic microglial clock modulates the inflammatory response, including the positive regulation of IL-6 expression in a particular pathological situation in the brain, GLIA 2016. GLIA 2017;65:198–208.

AB - Similar to neurons, microglia have an intrinsic molecular clock. The master clock oscillator Bmal1 modulates interleukin-6 upregulation in microglial cells exposed to lipopolysaccharide. Bmal1 can play a role in microglial inflammatory responses. We previously demonstrated that gliotransmitter ATP induces transient expression of the clock gene Period1 via P2X7 purinergic receptors in cultured microglia. In this study, we further investigated mechanisms underlying the regulation of pro-inflammatory cytokine production by clock molecules in microglial cells. Several clock gene transcripts exhibited oscillatory diurnal rhythmicity in microglial BV-2 cells. Real-time luciferase monitoring also showed diurnal oscillatory luciferase activity in cultured microglia from Per1::Luciferase transgenic mice. Lipopolysaccharide (LPS) strongly induced the expression of pro-inflammatory cytokines in BV-2 cells, whereas an siRNA targeting Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), a core positive component of the microglial molecular clock, selectively inhibited LPS-induced interleukin-6 (IL-6) expression. In addition, LPS-induced IL-6 expression was attenuated in microglia from Bmal1-deficient mice. This phenotype was recapitulated by pharmacological disruption of oscillatory diurnal rhythmicity using the synthetic Rev-Erb agonist SR9011. Promoter analysis of the Il6 gene revealed that Bmal1 is required for LPS-induced IL-6 expression in microglia. Mice conditionally Bmal1 deficient in cells expressing CD11b, including microglia, exhibited less potent upregulation of Il6 expression following middle cerebral artery occlusion compared with that in control mice, with a significant attenuation of neuronal damage. These results suggest that the intrinsic microglial clock modulates the inflammatory response, including the positive regulation of IL-6 expression in a particular pathological situation in the brain, GLIA 2016. GLIA 2017;65:198–208.

KW - Bmal1

KW - clock genes

KW - IL-6

KW - microglia

UR - http://www.scopus.com/inward/record.url?scp=84991070837&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84991070837&partnerID=8YFLogxK

U2 - 10.1002/glia.23087

DO - 10.1002/glia.23087

M3 - Article

VL - 65

SP - 198

EP - 208

JO - GLIA

JF - GLIA

SN - 0894-1491

IS - 1

ER -