학술논문
Circadian dependency of microglial heme oxygenase-1 expression and inflammation determine neuronal injury in hemorrhagic stroke.
Document Type
Academic Journal
Author
Henrich L; Department of Anesthesiology & Critical Care, Medical Center, University of Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Kiessling I; Department of Anesthesiology & Critical Care, Medical Center, University of Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Steimer M; Department of Anesthesiology & Critical Care, Medical Center, University of Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Frase S; Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Department of Neurology and Neuroscience, Medical Center, University of Freiburg, Freiburg, Germany.; Kaiser S; Department of Anesthesiology & Critical Care, Medical Center, University of Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Schallner N; Department of Anesthesiology & Critical Care, Medical Center, University of Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany. nils.schallner@uniklinik-freiburg.de.; Faculty of Medicine, University of Freiburg, Freiburg, Germany. nils.schallner@uniklinik-freiburg.de.
Source
Publisher: BioMed Central Country of Publication: England NLM ID: 101232234 Publication Model: Electronic Cited Medium: Print ISSN: 1476-9255 (Print) Linking ISSN: 14769255 NLM ISO Abbreviation: J Inflamm (Lond) Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
1476-9255
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 Hmox1fl/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-Hmox1fl/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.
(© 2023. The Author(s).)
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
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
Conclusions: Our data point towards a crucial role for the HO-1 enzyme system and circadian control in neuronal injury after a hemorrhagic stroke.
(© 2023. The Author(s).)