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

doi:10.1002/glia.23087

Cited by 60 publications

(69 citation statements)

References 48 publications

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“…Despite the wealth of information regarding Rev-erbα in peripheral immune function, little is known about its role in innate immune responses in the brain. Microglia exhibit robust circadian clock function and inflammatory activation of microglia varies in a circadian manner (41,42). Thus, loss of rhythmic Rev-erbαmediated transcriptional repression could play a key role in the regulation of the microglial activation state, as demonstrated by our finding that microglial Iba1 volume changes with time of day in a Rev-erbα-dependent manner.…”

Section: Discussionmentioning

confidence: 66%

Circadian clock protein Rev-erbα regulates neuroinflammation

Griffin

Dimitry

Sheehan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

196

192

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Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα −/− mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα −/− mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα −/− microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Reverbα physically interacts with the promoter regions of several NF-κB-related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Reverbα −/− mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPSinduced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Reverbα −/− mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.Rev-erbα | circadian | microglia | neuroinflammation C ircadian clocks allow organisms to precisely synchronize internal physiological processes with their external environment. A conserved transcriptional-translational feedback loop known as the core circadian clock controls cycles of protein expression that produce transcriptional and physiologic rhythms. This core circadian clock consists of the transcriptional activators BMAL1 and CLOCK, which drive transcription of their own transcriptional repressors, including CRYPTOCHROME (CRY), PE-RIOD (PER), and REV-ERB proteins (1). The circadian system regulates a variety of critical cellular processes, including aspects of metabolism, inflammation, and redox homeostasis (2). Disruptions of the clock or its associated proteins have been implicated in pathological conditions ranging from cancer to neurodegenerative diseases (2-4). However, the roles of cellular circadian clocks in brain health and neuroinflammation are still poorly understood.Aberrant glial cell activation and neuroinflammation are hallmarks of many neuro...

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Section: Discussionmentioning

confidence: 66%

Circadian clock protein Rev-erbα regulates neuroinflammation

Griffin

Dimitry

Sheehan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

196

192

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“…Intrinsic clock genes are thought to cause circadian changes in microglial activity such as proinflammatory responses (Fonken et al, ; Hayashi et al, ; Nakazato et al, ). However, we suspected that NA is involved in the regulation of microglial synapse elimination during sleep.…”

Section: Discussionmentioning

confidence: 99%

Phagocytic elimination of synapses by microglia during sleep

Choudhury

Miyanishi

Tamano

et al. 2019

Glia

107

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Synaptic strength reduces during sleep, but the underlying mechanisms of this process are unclear. This study showed reduction of synaptic proteins in rat prefrontal cortex (PFC) at AM7 or Zeitgeber Time (ZT0), when the light phase or sleeping period for rats started. At this time point, microglia were weakly activated, displaying larger and more granular somata with increased CD11b expression compared with those at ZT12, as revealed by flow cytometry. Expression of opsonins, such as complements or MFG‐E8, matrix metalloproteinases, and microglial markers at ZT0 were increased compared with that at ZT12. Microglia at ZT0 phagocytosed synapses, as revealed by immunohistochemical staining. Immunoblotting detected more synapsin I in the isolated microglia at ZT0 than at ZT12. Complement C3‐ or MFG‐E8‐bound synapses were the most abundant at ZT0, some of which were phagocytosed by microglia. Systemic administration of synthetic glucocorticoid dexamethasone reduced microglial size, granularity and CD11b expression at ZT0, resembling microglia at ZT12, and increased synaptic proteins and decreased the sleeping period. Noradrenaline (NA) suppressed glutamate‐induced phagocytosis in primary cultured microglia. Systemic administration of the brain monoamine‐depleting agent reserpine decreased NA content and synapsin I expression in PFC, and increased expression of microglia markers, C3 and MFG‐E8, while increasing the sleeping period. A NA precursor l‐threo‐dihydroxyphenylserine abolished the reserpine‐induced changes. These results suggest that microglia may eliminate presumably weak synapses during every sleep phase. The circadian changes in concentrations of circulating glucocorticoids and brain NA might be correlated with the circadian changes of microglial phenotypes and synaptic strength.

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“…The results of this study found that elevated IL-6 levels correlated with higher KYNA values in schizophrenia. This cytokine exerts an effect on different proinflammatory mechanisms in microglial cells [50,51] like microglia priming-i.e., the transition from resting to activated state [63]; regulation of the inflammatory response [64]; and overproduction of IL-6 in the aged brain [65]. Due to these microglial functions, authors pointed out that IL-6 was associated with KYNA production by increasing this metabolite in patients with schizophrenia [19].…”

Section: Il-6mentioning

confidence: 99%

Effects of inflammation on the kynurenine pathway in schizophrenia — a systematic review

Pedraz-Petrozzi

Elyamany

Rummel

et al. 2020

J Neuroinflammation

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Background: In the last decade, there has been growing evidence that an interaction exists between inflammation and the kynurenine pathway in schizophrenia. Additionally, many authors found microglial activation in cases of schizophrenia due to inflammatory mechanisms related mostly to an increase of pro-inflammatory cytokines. In order to gain new insights into the pathophysiology of schizophrenia, it is important to incorporate the latest published evidence concerning inflammatory mechanisms and kynurenine metabolism. This systematic review aims to collect reliable recent findings within the last decade supporting such a theory. Methods: A structured search of electronic databases was conducted for publications between 2008 and 2018 to identify eligible studies investigating patients with schizophrenia/psychosis and the relationship between inflammation and kynurenine pathway. Applicable studies were systematically scored using the NIH Quality Assessment Tools. Two researchers independently extracted data on diagnosis (psychosis/schizophrenia), inflammation, and kynurenine/tryptophan metabolites. Results: Ten eligible articles were identified where seven studies assessed blood samples and three assessed cerebrospinal fluid in schizophrenic patients. Of these articles: Four investigated the relationship between immunoglobulins and the kynurenine pathway and found correlations between IgA-mediated responses and levels of tryptophan metabolites (i.e., kynurenine pathway). Five examined the correlation between cytokines and kynurenine metabolites where three showed a relationship between elevated IL-6, TNF-α concentrations, and the kynurenine pathway. Only one study discovered correlations between IL-8 and the kynurenine pathway. Two studies showed correlations with lower concentrations of IL-4 and the kynurenine pathway. Moreover, this systematic review did not find a significant correlation between CRP (n = 1 study), IFN-γ (n = 3 studies), and the kynurenine pathway in schizophrenia.

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The intrinsic microglial clock system regulates interleukin‐6 expression

Cited by 60 publications

References 48 publications

Circadian clock protein Rev-erbα regulates neuroinflammation

Circadian clock protein Rev-erbα regulates neuroinflammation

Phagocytic elimination of synapses by microglia during sleep

Effects of inflammation on the kynurenine pathway in schizophrenia — a systematic review

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