Circadian Dependency of Microglial Heme Oxygenase-1 Expression and Inflammation Determine Neuronal Injury in Hemorrhagic Stroke

Overview

Journal J Inflamm (Lond)

Publisher Biomed Central

Date 2023 Dec 16

PMID 38104143

Authors

Luise Henrich

Iva Kiessling

Matti Steimer

Sibylle Frase

Sandra Kaiser

Nils Schallner

Affiliations

Soon will be listed here.

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 and LyzM-Cre-Hmox1 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 and LyzM-Cre-Hmox1 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 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.

Citing Articles

Severity of Repetitive Mild Traumatic Brain Injury Depends on Microglial Heme Oxygenase-1 and Carbon Monoxide.

Kaiser S, Fritsch A, Jakob L, Schallner N Eur J Neurosci. 2025; 61(2):e16666.

PMID: 39844588 PMC: 11755003. DOI: 10.1111/ejn.16666.

Pharmacological Approaches to Hearing Loss.

Cederroth C, Dyhrfjeld-Johnsen J, Canlon B Pharmacol Rev. 2024; 76(6):1063-1088.

PMID: 39164117 PMC: 11549935. DOI: 10.1124/pharmrev.124.001195.

References

Barahona R, Morabito S, Swarup V, Green K . Cortical diurnal rhythms remain intact with microglial depletion. Sci Rep. 2022; 12(1):114. PMC: 8742049. DOI: 10.1038/s41598-021-04079-w. View

Hijdra A, Brouwers P, Vermeulen M, van Gijn J . Grading the amount of blood on computed tomograms after subarachnoid hemorrhage. Stroke. 1990; 21(8):1156-61. DOI: 10.1161/01.str.21.8.1156. View

Garland P, Morton M, Haskins W, Zolnourian A, Durnford A, Gaastra B . Haemoglobin causes neuronal damage which is preventable by haptoglobin. Brain Commun. 2020; 2(1):fcz053. PMC: 7188517. DOI: 10.1093/braincomms/fcz053. View

Eckle T, Hartmann K, Bonney S, Reithel S, Mittelbronn M, Walker L . Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. Nat Med. 2012; 18(5):774-82. PMC: 3378044. DOI: 10.1038/nm.2728. View

Shimada Y, Tsunoda H, Zang L, Hirano M, Oka T, Tanaka T . Synergistic induction of heme oxygenase-1 by nicaraven after subarachnoid hemorrhage to prevent delayed cerebral vasospasm. Eur J Pharmacol. 2009; 620(1-3):16-20. DOI: 10.1016/j.ejphar.2009.08.009. View

Frase S, Kaiser S, Steimer M, Selzner L, Foit N, Niesen W . Patients with Subarachnoid Hemorrhage Exhibit Disturbed Expression Patterns of the Circadian Rhythm Gene . Life (Basel). 2021; 11(2). PMC: 7915417. DOI: 10.3390/life11020124. View

Clark J, Foresti R, Sarathchandra P, Kaur H, Green C, Motterlini R . Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction. Am J Physiol Heart Circ Physiol. 2000; 278(2):H643-51. DOI: 10.1152/ajpheart.2000.278.2.H643. View

Zhang R, Lahens N, Ballance H, Hughes M, Hogenesch J . A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci U S A. 2014; 111(45):16219-24. PMC: 4234565. DOI: 10.1073/pnas.1408886111. View

Panda S, Antoch M, Miller B, Su A, Schook A, Straume M . Coordinated transcription of key pathways in the mouse by the circadian clock. Cell. 2002; 109(3):307-20. DOI: 10.1016/s0092-8674(02)00722-5. View

10.

Zhang F, Wang S, Zhang M, Weng Z, Li P, Gan Y . Pharmacological induction of heme oxygenase-1 by a triterpenoid protects neurons against ischemic injury. Stroke. 2012; 43(5):1390-7. PMC: 3335928. DOI: 10.1161/STROKEAHA.111.647420. View

11.

Lu H, Shi J, Chen H, Hang C, Wang H, Yin H . Expression of monocyte chemoattractant protein-1 in the cerebral artery after experimental subarachnoid hemorrhage. Brain Res. 2009; 1262:73-80. DOI: 10.1016/j.brainres.2009.01.017. View

12.

LeBlanc 3rd R, Chen R, Selim M, Hanafy K . Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine. J Neuroinflammation. 2016; 13(1):244. PMC: 5020472. DOI: 10.1186/s12974-016-0709-1. View

13.

Marelli G, Erreni M, Anselmo A, Taverniti V, Guglielmetti S, Mantovani A . Heme-oxygenase-1 Production by Intestinal CX3CR1 Macrophages Helps to Resolve Inflammation and Prevents Carcinogenesis. Cancer Res. 2017; 77(16):4472-4485. DOI: 10.1158/0008-5472.CAN-16-2501. View

14.

Kaiser S, Selzner L, Weber J, Schallner N . Carbon monoxide controls microglial erythrophagocytosis by regulating CD36 surface expression to reduce the severity of hemorrhagic injury. Glia. 2020; 68(11):2427-2445. DOI: 10.1002/glia.23864. View

15.

Dioum E, Rutter J, Tuckerman J, Gonzalez G, Gilles-Gonzalez M, McKnight S . NPAS2: a gas-responsive transcription factor. Science. 2002; 298(5602):2385-7. DOI: 10.1126/science.1078456. View

16.

Chen-Roetling J, Kamalapathy P, Cao Y, Song W, Schipper H, Regan R . Astrocyte heme oxygenase-1 reduces mortality and improves outcome after collagenase-induced intracerebral hemorrhage. Neurobiol Dis. 2017; 102:140-146. PMC: 5604234. DOI: 10.1016/j.nbd.2017.03.008. View

17.

Steimer M, Kaiser S, Ulbrich F, Kalbhenn J, Burkle H, Schallner N . Expression of HO1 and PER2 can predict the incidence of delirium in trauma patients with concomitant brain injury. Sci Rep. 2021; 11(1):15388. PMC: 8319290. DOI: 10.1038/s41598-021-94773-6. View

18.

Temes R, Bleck T, Dugar S, Ouyang B, Mohammad Y, John S . Circadian variation in ictus of aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2011; 16(2):219-23. DOI: 10.1007/s12028-011-9640-6. View

19.

Minegishi S, Sagami I, Negi S, Kano K, Kitagishi H . Circadian clock disruption by selective removal of endogenous carbon monoxide. Sci Rep. 2018; 8(1):11996. PMC: 6086871. DOI: 10.1038/s41598-018-30425-6. View

20.

Karatsoreos I, Bhagat S, Bloss E, Morrison J, McEwen B . Disruption of circadian clocks has ramifications for metabolism, brain, and behavior. Proc Natl Acad Sci U S A. 2011; 108(4):1657-62. PMC: 3029753. DOI: 10.1073/pnas.1018375108. View