Neutrophil Enzyme Myeloperoxidase Modulates Neuronal Response in a Model of Subarachnoid Hemorrhage by Venous Injury.
Animals
Astrocytes
/ pathology
Calcium Signaling
Cerebral Veins
/ injuries
Cognition Disorders
/ etiology
Hydrogen Peroxide
/ cerebrospinal fluid
Inflammation
/ pathology
Maze Learning
Memory Disorders
/ etiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Neuroglia
/ enzymology
Neurons
/ pathology
Neutrophils
/ enzymology
Peroxidase
/ genetics
Spatial Memory
Subarachnoid Hemorrhage
/ pathology
astrocytes
brain
microglia
neutrophil
peroxidase
subarachnoid hemorrhage
Journal
Stroke
ISSN: 1524-4628
Titre abrégé: Stroke
Pays: United States
ID NLM: 0235266
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
pubmed:
19
8
2021
medline:
7
1
2022
entrez:
18
8
2021
Statut:
ppublish
Résumé
Aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits. Neutrophil infiltration into the central nervous system is linked to the development of these deficits after SAH. It is however unclear how neutrophil activity influences central nervous system function in SAH. The present project aims to elucidate which neutrophil factors mediate central nervous system injury and cognitive deficits after SAH. Using a murine model of SAH and mice deficient in neutrophil effector functions, we determined which neutrophil effector function is critical to the development of deficits after SAH. In vivo and in vitro techniques were used to investigate possible pathways of neutrophils effect after SAH. Our results show that mice lacking functional MPO (myeloperoxidase), a neutrophil enzyme, lack both the meningeal neutrophil infiltration (wild type, sham 872 cells/meninges versus SAH 3047, P=0.023; myeloperoxidase knockout [MPOKO], sham 1677 versus SAH 1636, P=NS) and erase the cognitive deficits on Barnes maze associated with SAH (MPOKO sham versus SAH, P=NS). The reintroduction of biologically active MPO, and its substrate hydrogen peroxide (H2O2), to the cerebrospinal fluid of MPOKO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH (time to goal box MPOKO sham versus MPOKO+MPO/H2O2, P=0.001). We find evidence of changes in neurons, astrocytes, and microglia with MPO/H2O2 suggesting the effect of MPO may have complex interactions with many cell types. Neurons exposed to MPO/H2O2 show decreased calcium activity at baseline and after stimulation with potassium chloride. Although astrocytes and microglia are affected, changes seen in astrocytes are most consistent with inflammatory changes that likely affect neurons. These results implicate MPO as a mediator of neuronal dysfunction in SAH through its effect on both neurons and glia. These results show that, in SAH, the activity of innate immune cells in the meninges modulates the activity and function of the underlying brain tissue.
Sections du résumé
Background and Purpose
Aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits. Neutrophil infiltration into the central nervous system is linked to the development of these deficits after SAH. It is however unclear how neutrophil activity influences central nervous system function in SAH. The present project aims to elucidate which neutrophil factors mediate central nervous system injury and cognitive deficits after SAH.
Methods
Using a murine model of SAH and mice deficient in neutrophil effector functions, we determined which neutrophil effector function is critical to the development of deficits after SAH. In vivo and in vitro techniques were used to investigate possible pathways of neutrophils effect after SAH.
Results
Our results show that mice lacking functional MPO (myeloperoxidase), a neutrophil enzyme, lack both the meningeal neutrophil infiltration (wild type, sham 872 cells/meninges versus SAH 3047, P=0.023; myeloperoxidase knockout [MPOKO], sham 1677 versus SAH 1636, P=NS) and erase the cognitive deficits on Barnes maze associated with SAH (MPOKO sham versus SAH, P=NS). The reintroduction of biologically active MPO, and its substrate hydrogen peroxide (H2O2), to the cerebrospinal fluid of MPOKO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH (time to goal box MPOKO sham versus MPOKO+MPO/H2O2, P=0.001). We find evidence of changes in neurons, astrocytes, and microglia with MPO/H2O2 suggesting the effect of MPO may have complex interactions with many cell types. Neurons exposed to MPO/H2O2 show decreased calcium activity at baseline and after stimulation with potassium chloride. Although astrocytes and microglia are affected, changes seen in astrocytes are most consistent with inflammatory changes that likely affect neurons.
Conclusions
These results implicate MPO as a mediator of neuronal dysfunction in SAH through its effect on both neurons and glia. These results show that, in SAH, the activity of innate immune cells in the meninges modulates the activity and function of the underlying brain tissue.
Identifiants
pubmed: 34404234
doi: 10.1161/STROKEAHA.120.033513
pmc: PMC8478903
mid: NIHMS1728772
doi:
Substances chimiques
Hydrogen Peroxide
BBX060AN9V
Peroxidase
EC 1.11.1.7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3374-3384Subventions
Organisme : NINDS NIH HHS
ID : R01 NS074997
Pays : United States
Organisme : NIH HHS
ID : R21 OD016562
Pays : United States
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