PMID- 38104143
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231219
IS  - 1476-9255 (Print)
IS  - 1476-9255 (Electronic)
IS  - 1476-9255 (Linking)
VI  - 20
IP  - 1
DP  - 2023 Dec 16
TI  - Circadian dependency of microglial heme oxygenase-1 expression and inflammation 
      determine neuronal injury in hemorrhagic stroke.
PG  - 43
LID - 10.1186/s12950-023-00371-w [doi]
LID - 43
AB  - 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.
CI  - (c) 2023. The Author(s).
FAU - Henrich, Luise
AU  - Henrich L
AD  - Department of Anesthesiology & Critical Care, Medical Center, University of 
      Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany.
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Kiessling, Iva
AU  - Kiessling I
AD  - Department of Anesthesiology & Critical Care, Medical Center, University of 
      Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany.
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Steimer, Matti
AU  - Steimer M
AD  - Department of Anesthesiology & Critical Care, Medical Center, University of 
      Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany.
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Frase, Sibylle
AU  - Frase S
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
AD  - Department of Neurology and Neuroscience, Medical Center, University of Freiburg, 
      Freiburg, Germany.
FAU - Kaiser, Sandra
AU  - Kaiser S
AD  - Department of Anesthesiology & Critical Care, Medical Center, University of 
      Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany.
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Schallner, Nils
AU  - Schallner N
AD  - Department of Anesthesiology & Critical Care, Medical Center, University of 
      Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany. 
      nils.schallner@uniklinik-freiburg.de.
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany. 
      nils.schallner@uniklinik-freiburg.de.
LA  - eng
PT  - Journal Article
DEP - 20231216
PL  - England
TA  - J Inflamm (Lond)
JT  - Journal of inflammation (London, England)
JID - 101232234
PMC - PMC10725034
OTO - NOTNLM
OT  - Brain Hemorrhage
OT  - Carbon Monoxide
OT  - Circadian rhythm
OT  - Heme Oxygenase
OT  - Microglia
OT  - Neuroinflammation
OT  - Phagocytosis
COIS- The authors declare that they have no competing interests.
EDAT- 2023/12/17 09:44
MHDA- 2023/12/17 09:45
PMCR- 2023/12/16
CRDT- 2023/12/16 23:27
PHST- 2023/06/26 00:00 [received]
PHST- 2023/12/13 00:00 [accepted]
PHST- 2023/12/17 09:45 [medline]
PHST- 2023/12/17 09:44 [pubmed]
PHST- 2023/12/16 23:27 [entrez]
PHST- 2023/12/16 00:00 [pmc-release]
AID - 10.1186/s12950-023-00371-w [pii]
AID - 371 [pii]
AID - 10.1186/s12950-023-00371-w [doi]
PST - epublish
SO  - J Inflamm (Lond). 2023 Dec 16;20(1):43. doi: 10.1186/s12950-023-00371-w.