Circadian dependency of microglial heme oxygenase-1 expression and inflammation determine neuronal injury in hemorrhagic stroke

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Abstract

Background

The heme oxygenase-1 (HO-1) enzyme pathway is of crucial importance in the removal of toxic blood components and regulation of neuroinflammation following hemorrhagic stroke. Although a circadian pattern dependency in the incidence and severity of hemorrhagic stroke exists, it is unknown whether the activity of the HO-1 system in the context of hemorrhagic injury also exhibits circadian dependency. We hypothesized that the circadian regulation of microglial HO-1 would determine the extent of neuroinflammation and neuronal injury in a murine model of subarachnoid hemorrhage (SAH).

Methods

In vitro expression patterns of HO-1 and circadian rhythm genes were analyzed in the microglial BV-2 cell line and primary microglia (PMG) using Western blot and qPCR. PMG isolated from Hmox1 ^fl/fl and LyzM-Cre-Hmox1 ^fl/fl mice were used to evaluate the role of microglial HO-1. We further investigated the in vivo relevance in a murine subarachnoid hemorrhage (SAH) model using Hmox1 ^fl/fl and LyzM-Cre-Hmox1 ^fl/fl mice with myeloid cell HO-1 deficiency, inducing SAH at different zeitgeber (ZT) times and analyzing the expression of HO-1 and the circadian control gene Period-2 (Per-2), respectively. Furthermore, we measured the inflammatory cytokine Monocyte Chemoattractant Protein-1 (MCP-1) in the cerebrospinal fluid of SAH patients in correlation with clinical outcome.

Results

HO-1 baseline expression and response to CO with blood exposure depended on ZT. In vitro expression of circadian control genes was de-synchronized in LyzM-Cre-Hmox1 ^fl/fl PMG and did not respond to exogenous CO exposure. We found that circadian rhythm plays a crucial role in brain damage after SAH. At ZT2, we observed less phagocytic function, more vasospasm and increased microglial activation. CO reduced mortality at ZT12 in HO-1 deficient mice and reduced the difference between ZT2 and ZT12 in the inflammatory response. Induction of MCP-1 in the CSF from SAH patients was time-dependent and correlated with the expression of circadian control genes, SAH severity, functional impairment and delirium.

Conclusions

Our data point towards a crucial role for the HO-1 enzyme system and circadian control in neuronal injury after a hemorrhagic stroke.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12950-023-00371-w.

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Most cited references 42

Record: found
Abstract: found
Article: not found

Coordinated transcription of key pathways in the mouse by the circadian clock.

Satchidananda Panda, Marina P. Antoch, Brooke H. Miller … (2002)

In mammals, circadian control of physiology and behavior is driven by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. We have used gene expression profiling to identify cycling transcripts in the SCN and in the liver. Our analysis revealed approximately 650 cycling transcripts and showed that the majority of these were specific to either the SCN or the liver. Genetic and genomic analysis suggests that a relatively small number of output genes are directly regulated by core oscillator components. Major processes regulated by the SCN and liver were found to be under circadian regulation. Importantly, rate-limiting steps in these various pathways were key sites of circadian control, highlighting the fundamental role that circadian clocks play in cellular and organismal physiology.

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Record: found
Abstract: found
Article: not found

A circadian gene expression atlas in mammals: implications for biology and medicine.

Ray Zhang, Nicholas Lahens, Heather I Ballance … (2014)

To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional "rush hours" preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spliceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.

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Article: not found

Disruption of circadian clocks has ramifications for metabolism, brain, and behavior.

Liam J. Morrison, B McEwen, Ilia N. Karatsoreos … (2011)

Circadian (daily) rhythms are present in almost all plants and animals. In mammals, a brain clock located in the hypothalamic suprachiasmatic nucleus maintains synchrony between environmental light/dark cycles and physiology and behavior. Over the past 100 y, especially with the advent of electric lighting, modern society has resulted in a round-the-clock lifestyle, in which natural connections between rest/activity cycles and environmental light/dark cycles have been degraded or even broken. Instances in which rapid changes to sleep patterns are necessary, such as transmeridian air travel, demonstrate negative effects of acute circadian disruption on physiology and behavior. However, the ramifications of chronic disruption of the circadian clock for mental and physical health are not yet fully understood. By housing mice in 20-h light/dark cycles, incongruous with their endogenous ∼24-h circadian period, we were able to model the effects of chronic circadian disruption noninvasively. Housing in these conditions results in accelerated weight gain and obesity, as well as changes in metabolic hormones. In the brain, circadian-disrupted mice exhibit a loss of dendritic length and decreased complexity of neurons in the prelimbic prefrontal cortex, a brain region important in executive function and emotional control. Disrupted animals show decreases in cognitive flexibility and changes in emotionality consistent with the changes seen in neural architecture. How our findings translate to humans living and working in chronic circadian disruption is unknown, but we believe that this model can provide a foundation to understand how environmental disruption of circadian rhythms impacts the brain, behavior, and physiology.

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Author and article information

Contributors

Nils Schallner: nils.schallner@uniklinik-freiburg.de

Journal

Journal ID (nlm-ta): J Inflamm (Lond)

Journal ID (iso-abbrev): J Inflamm (Lond)

Title: Journal of Inflammation (London, England)

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-9255

Publication date (Electronic): 16 December 2023

Publication date PMC-release: 16 December 2023

Publication date Collection: 2023

Volume: 20

Electronic Location Identifier: 43

Affiliations

[1 ]Department of Anesthesiology & Critical Care, Medical Center, University of Freiburg, ( https://ror.org/0245cg223) Hugstetter Str. 55, Freiburg, 79106 Germany

[2 ]Faculty of Medicine, University of Freiburg, ( https://ror.org/0245cg223) Freiburg, Germany

[3 ]Department of Neurology and Neuroscience, Medical Center, University of Freiburg, ( https://ror.org/0245cg223) Freiburg, Germany

Article

Publisher ID: 371

DOI: 10.1186/s12950-023-00371-w

PMC ID: 10725034

PubMed ID: 38104143

SO-VID: 9ac38371-ae23-45b6-af8e-aeac89babeb1

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 26 June 2023

Date accepted : 13 December 2023

Funding

Funded by: Universitätsklinikum Freiburg (8975)

Open Access :

Open Access funding enabled and organized by Projekt DEAL.

Custom metadata

ScienceOpen disciplines: Immunology

Keywords: circadian rhythm,carbon monoxide,heme oxygenase,microglia,phagocytosis,brain hemorrhage,neuroinflammation

Data availability:

ScienceOpen disciplines: Immunology

Keywords: circadian rhythm, carbon monoxide, heme oxygenase, microglia, phagocytosis, brain hemorrhage, neuroinflammation

Circadian dependency of microglial heme oxygenase-1 expression and inflammation determine neuronal injury in hemorrhagic stroke

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Abstract

Background

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Conclusions

Supplementary Information

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Most cited references 42

Coordinated transcription of key pathways in the mouse by the circadian clock.

A circadian gene expression atlas in mammals: implications for biology and medicine.

Disruption of circadian clocks has ramifications for metabolism, brain, and behavior.

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