Role of Lipocalin-2 in Brain Injury after Intracerebral Hemorrhage

Lipocalin-2 (LCN2) is a siderophore-binding protein involved in cellular iron transport and neuroinflammation. Both iron and inflammation are involved in brain injury after intracerebral hemorrhage (ICH) and this study examined the role of LCN2 in such injury. Male adult C57BL/6 wild-type (WT) or LCN2-deficient (LCN2-/-) mice had an intracerebral injection of autologous blood or FeCl2. Control animals had a sham operation or saline injection. T2-weighted magnetic resonance imaging and behavioral tests were performed at days 1, 3, 7, 14, and 28 after injection. In WT mice, brain LCN2 levels were increased in the ipsilateral basal ganglia after ICH or iron injection. Lipocalin-2-positive cells were astrocytes, microglia, neurons, and endothelial cells. Intracerebral hemorrhage resulted in a significant increase in ferritin expression in the ipsilateral basal ganglia. Compared with WT mice, ICH caused less ferritin upregulation, microglia activation, brain swelling, brain atrophy, and neurologic deficits in LCN2-/- mice ( P < 0.05). The size of the lesion induced by FeCl2 injection as well as the degree of brain swelling and blood–brain barrier disruption were also less in LCN2-/- mice ( P < 0.05). These results suggest a role of LCN2 in enhancing brain injury and iron toxicity after ICH.

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IL (Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates Brain Injury Following Intracerebral Hemorrhage

Stroke ◽

10.1161/strokeaha.119.028638 ◽

2020 ◽

Vol 51 (3) ◽

pp. 967-974 ◽

Cited By ~ 9

Author(s):

Samuel X. Shi ◽

Yu-Jing Li ◽

Kaibin Shi ◽

Kristofer Wood ◽

Andrew F. Ducruet ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Autologous Blood ◽

Brain Slices ◽

Neurological Deficits ◽

Transgenic Mouse Line ◽

Il Interleukin ◽

Targeted Expression ◽

Interleukin 15

Background and Purpose— Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods— Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15 tg ). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results— In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15 tg mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15 tg mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1β, and TNF-α is markedly increased in GFAP-IL-15 tg mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15 tg mice. Conclusions— Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.

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Autophagy after Experimental Intracerebral Hemorrhage

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600578 ◽

2007 ◽

Vol 28 (5) ◽

pp. 897-905 ◽

Cited By ~ 79

Author(s):

Yangdong He ◽

Shu Wan ◽

Ya Hua ◽

Richard F Keep ◽

Guohua Xi

Keyword(s):

Cell Death ◽

Brain Injury ◽

Basal Ganglia ◽

Intracerebral Hemorrhage ◽

Cathepsin D ◽

Cell Types ◽

Sprague Dawley ◽

Male Adult ◽

Double Labeling ◽

Autologous Whole Blood

Autophagy contributes to ischemic brain injury, but it is not clear if autophagy occurs after intracerebral hemorrhage (ICH). This study examined whether ICH-induced cell death is partly autophagic. It then examined the role of iron in inducing this form of cell death after ICH. Male, adult Sprague-Dawley rats received an infusion of autologous whole blood or ferrous iron into the right basal ganglia. Control rats (sham) had a needle insertion. The rats were killed at 1, 3, 7, or 28 days later. Some rats were treated with either deferoxamine or vehicle after ICH. Microtubule-associated protein light chain-3 (LC3), a biomarker of autophagosome, and cathepsin D, a lysosomal biomarker, were measured by Western blot analysis and immunohistochemistry. Immunofluorescent double-labeling was used to identify the cell types expressing cathepsin D. Electron microscopy was performed to examine the cellular ultrastructure changes after ICH. We found that conversion of LC3-I to LC3-II, cathepsin D expression, and vacuole formation are increased in the ipsilateral basal ganglia after ICH. Intracerebral infusion of iron also resulted in enhanced conversion of LC3-I to LC3-II and increased cathepsin D levels. Deferoxamine (an iron chelator) treatment significantly reduced the conversion of LC3-I to LC3-II and cathepsin D levels after ICH. Our results demonstrated that autophagy occurs after ICH, and iron has a key role in ICH-induced autophagy. This also suggests that iron-induced autophagy may play a role in brain injury in other diseases associated with iron overload.

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Histone Deacetylase Inhibitor Scriptaid Alleviated Neurological Dysfunction after Experimental Intracerebral Hemorrhage in Mice

Behavioural Neurology ◽

10.1155/2018/6583267 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Heng Yang ◽

Wei Ni ◽

Hanqiang Jiang ◽

Yu Lei ◽

Jiabin Su ◽

...

Keyword(s):

Brain Injury ◽

White Matter ◽

Basal Ganglia ◽

Intracerebral Hemorrhage ◽

Autologous Blood ◽

White Matter Injury ◽

Neurological Dysfunction ◽

Vehicle Group ◽

Hematoma Volume ◽

The Right

Objectives. To investigate the role of Scriptaid in reducing brain injury after intracerebral hemorrhage (ICH) in mice. Methods. An ICH model was constructed by injecting autologous blood into the right basal ganglia in mice. The animals were administered 3.5 mg/kg of Scriptaid intraperitoneally after ICH. The hematoma volume and hemoglobin level were measured to examine hematoma resolution. A behavior test and brain edema and white matter injury examinations indicated brain injury after ICH. Results. Scriptaid treatment promoted hematoma resolution and reduced the hematoma volume 7 d after ICH compared with the vehicle group (P<0.05). Scriptaid treatment also alleviated the brain water content in the ipsilateral basal ganglia (P<0.05) and cortex (P<0.01) 3 d after ICH. In addition, Scriptaid improved neurological function recovery and alleviated white matter injury 35 d after ICH. Conclusions. Scriptaid can protect against brain injury after ICH and may be considered a new medical therapy method for ICH.

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The role of complement in brain injury following intracerebral hemorrhage: A review

Experimental Neurology ◽

10.1016/j.expneurol.2021.113654 ◽

2021 ◽

pp. 113654

Author(s):

Katherine Holste ◽

Fan Xia ◽

Hugh J.L. Garton ◽

Shu Wan ◽

Ya Hua ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage

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Abstract TP351: Axl/Mer Receptor Tyrosine Kinase Mediates Erythrophagocytosis-Induced Macrophage Reparative Phenotype and Brain Recovery in Experimental Intracerebral Hemorrhage

Stroke ◽

10.1161/str.48.suppl_1.tp351 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Che-Feng Chang ◽

Brittany A Thomas ◽

Michael Askenase ◽

Arthur F Steinschneider ◽

Youxi Ai ◽

...

Keyword(s):

Bone Marrow ◽

Brain Injury ◽

Intracerebral Hemorrhage ◽

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Autologous Blood ◽

Phenotypic Change ◽

Macrophage Phenotype ◽

Double Knockout ◽

Brain Recovery

Introduction: Local inflammation contributes to both brain injury and recovery after intracerebral hemorrhage (ICH). Our previous studies have shown brain-infiltrating macrophages (BIMs) aggravate early brain injury after ICH; however, BIMs increase scavenger receptor CD36 levels over time, and hematoma clearance is delayed in the absence of BIMs. The mechanism that mediates BIMs phenotypic change in the ICH brain is elusive. In this study, we delineate the dynamic transcriptome profile of BIMs after ICH and test potential mediator that might modulate BIMs polarity in ICH. Methods: Autologous blood injection ICH model and thrombin-treated bone marrow-derived macrophages (BMDM) were used to mimic ICH in vivo and in vitro . BIMs were isolated by FACS, and the 780 transcriptome of BIMs were determined using NanoString. Flow cytometry and RT-qPCR were performed to detect the frequency of phosphatidylserine-positive (eryptotic) RBCs and to assess BIMs phenotype in the perihematomal tissue. Erythrophagocytosis of eryptotic RBCs was identified by immunofluorescence and microscopy. Neurologic deficit was evaluated by cylinder test. Axl/Mer receptor tyrosine kinase double knockout (AM DKO) mice, AM DKO bone-marrow chimeras, and AM DKO BMDM were used to evaluate the function of Axl/Mer on macrophage phenotype and on brain recovery after ICH. Results: BIMs highly expressed proinflammatory transcripts such as cd86 , tlr2 , nlrp3 , and tnf at days 1 and 3 post-ICH; these were decreased at days 7 and 10. Transcripts relevant to efferocytosis ( axl ) and lysosome formation ( cd63 ) increased from days 3 to 10 post-ICH. At days 1 and 3, phosphatidylserine levels was increased on RBCs in the ICH brain. Engulfment of eryptotic RBCs reduced proinflammatory phenotype of BMDM. Thrombin-stimulated AM DKO BMDM had reduced erythrophagocytosis ability and increased tnf and il-6 gene expression. AM DKO mice and AM DKO chimeras had low CD36 and high MHC II levels on BIMs and had worse functional outcome after ICH. Conclusions: BIMs initially express proinflammatory phenotype and then switch to a reparative phenotype after ICH. Axl/Mer is involved in regulation of macrophage polarity through modulating erythrophagocytosis ability and contributes to ICH brain recovery.

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Correction to: Intracerebral Hemorrhage–Induced Brain Injury in Rats: the Role of Extracellular Peroxiredoxin 2

Translational Stroke Research ◽

10.1007/s12975-019-00720-z ◽

2019 ◽

Vol 11 (6) ◽

pp. 1364-1365

Author(s):

Liheng Bian ◽

Jingwei Zhang ◽

Ming Wang ◽

Richard F. Keep ◽

Guohua Xi ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Peroxiredoxin 2

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α7 Nicotinic Acetylcholine Receptor Stimulation Attenuates Neuroinflammation through JAK2-STAT3 Activation in Murine Models of Intracerebral Hemorrhage

BioMed Research International ◽

10.1155/2017/8134653 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 10

Author(s):

Paul R. Krafft ◽

Devin McBride ◽

William B. Rolland ◽

Tim Lekic ◽

Jerry J. Flores ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Treatment Effects ◽

Autologous Blood ◽

Janus Kinase ◽

Intracerebral Injection ◽

Sprague Dawley ◽

Nicotinic Acetylcholine

Accounting for high mortality and morbidity rates, intracerebral hemorrhage (ICH) remains one of the most detrimental stroke subtypes lacking a specific therapy. Neuroinflammation contributes to ICH-induced brain injury and is associated with unfavorable outcomes. This study aimed to evaluate whetherα7 nicotinic acetylcholine receptor (α7nAChR) stimulation ameliorates neuroinflammation after ICH. Male CD-1 mice and Sprague-Dawley were subjected to intracerebral injection of autologous blood or bacterial collagenase. ICH animals received eitherα7nAChR agonist PHA-543613 alone or combined withα7nAChR antagonist methyllycaconitine (MLA) or Janus kinase 2 (JAK2) antagonist AG490. Neurobehavioral deficits were evaluated at 24 hours, 72 hours, and 10 weeks after ICH induction. Perihematomal expressions of JAK2, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor-α(TNF-α), and myeloperoxidase (MPO) were quantified via Western blot. Histologic volumetric analysis of brain tissues was conducted after 10 weeks following ICH induction. PHA-543613 improved short-term neurobehavioral (sensorimotor) deficits and increased activated perihematomal JAK2 and STAT3 expressions while decreasing TNF-αand MPO expressions after ICH. MLA reversed these treatment effects. PHA-543613 also improved long-term neurobehavioral (sensorimotor, learning, and memory) deficits and ameliorated brain atrophy after ICH. These treatment effects were reduced by AG490.α7nAChR stimulation reduced neuroinflammation via activation of the JAK2-STAT3 pathway, thereby ameliorating the short- and long-term sequelae after ICH.

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Intracerebral Hemorrhage–Induced Brain Injury in Rats: the Role of Extracellular Peroxiredoxin 2

Translational Stroke Research ◽

10.1007/s12975-019-00714-x ◽

2019 ◽

Vol 11 (2) ◽

pp. 288-295 ◽

Cited By ~ 6

Author(s):

Liheng Bian ◽

Jingwei Zhang ◽

Ming Wang ◽

Richard F. Keep ◽

Guohua Xi ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Peroxiredoxin 2

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Spreading depolarizations in patients with spontaneous intracerebral hemorrhage: Association with perihematomal edema progression

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16651269 ◽

2016 ◽

Vol 37 (5) ◽

pp. 1871-1882 ◽

Cited By ~ 16

Author(s):

Raimund Helbok ◽

Alois Josef Schiefecker ◽

Christian Friberg ◽

Ronny Beer ◽

Mario Kofler ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Electrode Placement ◽

Secondary Brain Injury ◽

Spontaneous Intracerebral Hemorrhage ◽

Strip Electrode ◽

Hematoma Evacuation ◽

Perihematomal Edema ◽

Pathophysiologic Mechanisms

Pathophysiologic mechanisms of secondary brain injury after intracerebral hemorrhage and in particular mechanisms of perihematomal-edema progression remain incompletely understood. Recently, the role of spreading depolarizations in secondary brain injury was established in ischemic stroke, subarachnoid hemorrhage and traumatic brain injury patients. Its role in intracerebral hemorrhage patients and in particular the association with perihematomal-edema is not known. A total of 27 comatose intracerebral hemorrhage patients in whom hematoma evacuation and subdural electrocorticography was performed were studied prospectively. Hematoma evacuation and subdural strip electrode placement was performed within the first 24 h in 18 patients (67%). Electrocorticography recordings started 3 h after surgery (IQR, 3–5 h) and lasted 157 h (median) per patient and 4876 h in all 27 patients. In 18 patients (67%), a total of 650 spreading depolarizations were observed. Spreading depolarizations were more common in the initial days with a peak incidence on day 2. Median electrocorticography depression time was longer than previously reported (14.7 min, IQR, 9–22 min). Postoperative perihematomal-edema progression (85% of patients) was significantly associated with occurrence of isolated and clustered spreading depolarizations. Monitoring of spreading depolarizations may help to better understand pathophysiologic mechanisms of secondary insults after intracerebral hemorrhage. Whether they may serve as target in the treatment of intracerebral hemorrhage deserves further research.

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