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The Immune System and Inflammation in Cerebral Ischemia

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2015) | Viewed by 80308

Special Issue Editors

Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia
Interests: stroke; brain inflammation; vascular biology; immunopharmacology; vascular disease; pharmacology
Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia
Interests: stroke; cerebral ischemia; middle cerebral artery occlusion; brain inflammation; Th1/Th2 balance; cytokines; vascular cognitive impairment

Special Issue Information

Dear Colleagues,

Stroke is a leading cause of death and morbidity worldwide, with over a third of survivors being left with major neurological injury. However, besides thrombolysis by intravenous recombinant tissue plasminogen activator, which is feasible in less than 10% of ischemic stroke patients, no other drug treatments are available. There is, therefore, a great need to better understand, so as to be able to more appropriately treat, the mechanisms underlying stroke-induced pathophysiology. It is now recognised that brain injury after stroke is followed by the induction of cytokines, which then attract and activate inflammatory cells belonging to both the innate and adaptive immune systems, to the damaged tissue. These cells can then impact, in a complex manner, the ultimate extent of brain injury and they may also cause serious systemic consequences. Thus, a more complete elucidation of stroke-related effects on the immune system, including the secondary phenomenon of post-stroke immunosuppression and bacterial infection, is desperately needed to identify new therapeutic strategies for limiting stroke injury and promoting recovery.

This Special Issue calls for original research, mini and full reviews, and perspectives that address the progress and current knowledge in the overlapping research topics of immunology and stroke. These include, but are not limited to the fields that are mentioned in the keywords.

Prof. Chris Sobey
Dr. Hyun Ah Kim
Guest Editors

Manuscript Submission Information

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Keywords

  • stroke
  • neurodegenerative diseases
  • immune system
  • inflammation
  • cytokines
  • lymphocytes
  • monocytes/macrophages
  • microglia
  • secondary brain injury
  • immunosuppression
  • post-stroke infection

Published Papers (11 papers)

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Research

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573 KiB  
Article
Key Immune Events of the Pathomechanisms of Early Cardioembolic Stroke: Multi-Database Mining and Systems Biology Approach
by Chia-Chou Wu and Bor-Sen Chen
Int. J. Mol. Sci. 2016, 17(3), 305; https://doi.org/10.3390/ijms17030305 - 27 Feb 2016
Cited by 5 | Viewed by 4908
Abstract
While inflammation has generally been regarded as a negative factor in stroke recovery, this viewpoint has recently been challenged by demonstrating that inflammation is a necessary and sufficient factor for regeneration in the zebrafish brain injury model. This close relationship with inflammation suggests [...] Read more.
While inflammation has generally been regarded as a negative factor in stroke recovery, this viewpoint has recently been challenged by demonstrating that inflammation is a necessary and sufficient factor for regeneration in the zebrafish brain injury model. This close relationship with inflammation suggests that a re-examination of the immune system’s role in strokes is necessary. We used a systems biology approach to investigate the role of immune-related functions via their interactions with other molecular functions in early cardioembolic stroke. Based on protein interaction models and on microarray data from the blood of stroke subjects and healthy controls, networks were constructed to delineate molecular interactions at four early stages (pre-stroke, 3 h, 5 h and 24 h after stroke onset) of cardioembolic stroke. A comparative analysis of functional networks identified interactions of immune-related functions with other molecular functions, including growth factors, neuro/hormone and housekeeping functions. These provide a potential pathomechanism for early stroke pathophysiology. In addition, several potential targets of miRNA and methylation regulations were derived based on basal level changes observed in the core networks and literature. The results provide a more comprehensive understanding of stroke progression mechanisms from an immune perspective and shed light on acute stroke treatments. Full article
(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)
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3251 KiB  
Article
Immunohistochemical Analysis of Cerebral Thrombi Retrieved by Mechanical Thrombectomy from Patients with Acute Ischemic Stroke
by Michael K. Schuhmann, Ignaz Gunreben, Christoph Kleinschnitz and Peter Kraft
Int. J. Mol. Sci. 2016, 17(3), 298; https://doi.org/10.3390/ijms17030298 - 26 Feb 2016
Cited by 56 | Viewed by 8329
Abstract
Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance [...] Read more.
Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance in stroke-related inflammation. We therefore histopathologically investigated 37 intracerebral thrombi mechanically retrieved from patients with AIS, and focused on the composition of immune cells and platelets. We also conducted correlation analyses of distinctive morphologic patterns (erythrocytic, serpentine, layered, red, white, mixed appearance) with clinical parameters. Most T cells and monocytes were detected in erythrocytic and red clots, in which the distribution of these cells was random. In contrast, von Willebrand factor (vWF)-positive areas co-localized with regions of fibrin and collagen. While clots with huge amounts of vWF seem to be associated with a high National Institute of Health Stroke Scale score at admission, histologic findings could not predict the clinical outcome at discharge. In summary, we provide the first histologic description of mechanically retrieved intracerebral thrombi regarding biomarkers relevant for inflammation in ischemic stroke. Full article
(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)
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3159 KiB  
Article
Erythropoietin Ameliorates Neonatal Hypoxia-Ischemia-Induced Neurobehavioral Deficits, Neuroinflammation, and Hippocampal Injury in the Juvenile Rat
by Kuo-Mao Lan, Lu-Tai Tien, Zhengwei Cai, Shuying Lin, Yi Pang, Sachiko Tanaka, Philip G. Rhodes, Abhay J. Bhatt, Renate D. Savich and Lir-Wan Fan
Int. J. Mol. Sci. 2016, 17(3), 289; https://doi.org/10.3390/ijms17030289 - 26 Feb 2016
Cited by 37 | Viewed by 6008
Abstract
The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)–P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which [...] Read more.
The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)–P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which is relevant to immature human infants. Sprague-Dawley rats at P5 were subjected to right common carotid artery ligation followed by an exposure to 6% oxygen with balanced nitrogen for 1.5 h. Human recombinant EPO (rEPO, at a dose of 5 units/g) was administered intraperitoneally one hour before or immediately after insult, followed by additional injections at 24 and 48 h post-insult. The control rats were injected with normal saline following HI. Neurobehavioral tests were performed on P8 and P20, and brain injury was examined on P21. HI insult significantly impaired neurobehavioral performance including sensorimotor, locomotor activity and cognitive ability on the P8 and P20 rats. HI insult also resulted in brain inflammation (as indicated by microglia activation) and neuronal death (as indicated by Jade B positive staining) in the white matter, striatum, cortex, and hippocampal areas of the P21 rat. Both pre- and post-treatment with rEPO significantly improved neurobehavioral performance and protected against the HI-induced neuronal death, microglia activation (OX42+) as well as loss of mature oligodendrocytes (APC-CC1+) and hippocampal neurons (Nissl+). The long-lasting protective effects of rEPO in the neonatal rat HI model suggest that to exert neurotrophic activity in the brain might be an effective approach for therapeutic treatment of neonatal brain injury induced by hypoxia-ischemia. Full article
(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)
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Article
Characterization of Peripheral Immune Cell Subsets in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study
by Peter Kraft, Christiane Drechsler, Michael K. Schuhmann, Ignaz Gunreben and Christoph Kleinschnitz
Int. J. Mol. Sci. 2015, 16(10), 25433-25449; https://doi.org/10.3390/ijms161025433 - 23 Oct 2015
Cited by 7 | Viewed by 5400
Abstract
Immune cells (IC) play a crucial role in murine stroke pathophysiology. However, data are limited on the role of these cells in ischemic stroke in humans. We therefore aimed to characterize and compare peripheral IC subsets in patients with acute ischemic stroke/transient ischemic [...] Read more.
Immune cells (IC) play a crucial role in murine stroke pathophysiology. However, data are limited on the role of these cells in ischemic stroke in humans. We therefore aimed to characterize and compare peripheral IC subsets in patients with acute ischemic stroke/transient ischemic attack (AIS/TIA), chronic cerebrovascular disease (CCD) and healthy volunteers (HV). We conducted a case-control study of patients with AIS/TIA (n = 116) or CCD (n = 117), and HV (n = 104) who were enrolled at the University Hospital Würzburg from 2010 to 2013. We determined the expression and quantity of IC subsets in the three study groups and performed correlation analyses with demographic and clinical parameters. The quantity of several IC subsets differed between the AIS/TIA, CCD, and HV groups. Several clinical and demographic variables independently predicted the quantity of IC subsets in patients with AIS/TIA. No significant changes in the quantity of IC subsets occurred within the first three days after AIS/TIA. Overall, these findings strengthen the evidence for a pathophysiologic role of IC in human ischemic stroke and the potential use of IC-based biomarkers for the prediction of stroke risk. A comprehensive description of IC kinetics is crucial to enable the design of targeted treatment strategies. Full article
(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)
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2755 KiB  
Article
Stromal Cell-Derived Factor-1α Plays a Crucial Role Based on Neuroprotective Role in Neonatal Brain Injury in Rats
by Miki Mori, Keiichi Matsubara, Yuko Matsubara, Yuka Uchikura, Hisashi Hashimoto, Toru Fujioka and Takashi Matsumoto
Int. J. Mol. Sci. 2015, 16(8), 18018-18032; https://doi.org/10.3390/ijms160818018 - 05 Aug 2015
Cited by 10 | Viewed by 5462
Abstract
Owing to progress in perinatal medicine, the survival of preterm newborns has markedly increased. However, the incidence of cerebral palsy has risen in association with increased preterm birth. Cerebral palsy is largely caused by cerebral hypoxic ischemia (HI), for which there are no [...] Read more.
Owing to progress in perinatal medicine, the survival of preterm newborns has markedly increased. However, the incidence of cerebral palsy has risen in association with increased preterm birth. Cerebral palsy is largely caused by cerebral hypoxic ischemia (HI), for which there are no effective medical treatments. We evaluated the effects of stromal cell-derived factor-1α (SDF-1α) on neonatal brain damage in rats. Left common carotid (LCC) arteries of seven-day-old Wistar rat pups were ligated, and animals were exposed to hypoxic gas to cause cerebral HI. Behavioral tests revealed that the memory and spatial perception abilities were disturbed in HI animals, and that SDF-1α treatment improved these cognitive functions. Motor coordination was also impaired after HI but was unimproved by SDF-1α treatment. SDF-1α reduced intracranial inflammation and induced cerebral remyelination, as indicated by the immunohistochemistry results. These data suggest that SDF-1α specifically influences spatial perception abilities in neonatal HI encephalopathy. Full article
(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)
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11386 KiB  
Article
Characterization of Behaviour and Remote Degeneration Following Thalamic Stroke in the Rat
by Nina Weishaupt, Patricia Riccio, Taylor Dobbs, Vladimir C. Hachinski and Shawn N. Whitehead
Int. J. Mol. Sci. 2015, 16(6), 13921-13936; https://doi.org/10.3390/ijms160613921 - 17 Jun 2015
Cited by 10 | Viewed by 5895
Abstract
Subcortical ischemic strokes are among the leading causes of cognitive impairment. Selective atrophy of remote brain regions connected to the infarct is thought to contribute to deterioration of cognitive functions. The mechanisms underlying this secondary degenerative process are incompletely understood, but are thought [...] Read more.
Subcortical ischemic strokes are among the leading causes of cognitive impairment. Selective atrophy of remote brain regions connected to the infarct is thought to contribute to deterioration of cognitive functions. The mechanisms underlying this secondary degenerative process are incompletely understood, but are thought to include inflammation. We induce ischemia by unilateral injection of endothelin-I into the rat dorsomedial thalamic nucleus, which has defined reciprocal connections to the frontal cortex. We use a comprehensive test battery to probe for changes in behaviour, including executive functions. After a four-week recovery period, brain sections are stained with markers for degeneration, microglia, astrocytes and myelin. Degenerative processes are localized within the stroke core and along the full thalamocortical projection, which does not translate into measurable behavioural deficits. Significant microglia recruitment, astrogliosis or myelin loss along the axonal projection or within the frontal cortex cannot be detected. These findings indicate that critical effects of stroke-induced axonal degeneration may only be measurable beyond a threshold of stroke severity and/or follow a different time course. Further investigations are needed to clarify the impact of inflammation accompanying axonal degeneration on delayed remote atrophy after stroke. Full article
(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)
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798 KiB  
Short Note
Association between Serum Soluble CD154 Levels and Mortality in Patients with Malignant Middle Cerebral Artery Infarction
by Leonardo Lorente, María M. Martín, Agustín F. González-Rivero, Luis Ramos, Mónica Argueso, Juan J. Cáceres, Jordi Solé-Violán, Alejandro Jiménez and Juan M. Borreguero-León
Int. J. Mol. Sci. 2015, 16(6), 12147-12158; https://doi.org/10.3390/ijms160612147 - 28 May 2015
Cited by 11 | Viewed by 4740
Abstract
Background: CD154 and its soluble counterpart (sCD154) are proteins of the tumor necrosis factor (TNF) family and exhibit proinflamatory and procoagulant properties. Higher circulating sCD154 levels have been found in ischemic stroke patients than in controls. However, the association between circulating sCD154 levels [...] Read more.
Background: CD154 and its soluble counterpart (sCD154) are proteins of the tumor necrosis factor (TNF) family and exhibit proinflamatory and procoagulant properties. Higher circulating sCD154 levels have been found in ischemic stroke patients than in controls. However, the association between circulating sCD154 levels and mortality in ischemic stroke patients has not been reported, and was the focus of this study. Methods: This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. We measured serum sCD154 from 50 patients with severe malignant middle cerebral artery infarction (MMCAI), defined as Glasgow Coma Scale (GCS) lower than 9, at the moment of the severe MMCAI diagnosis and from 50 healthy controls. The end-point of the study was 30-day mortality. Results: We found higher serum sCD154 levels in patients with severe MMCAI than in healthy controls (p < 0.001). We found higher serum sCD154 levels (p < 0.001) in non-surviving (n = 26) than in surviving MMCAI patients (n = 24). Multiple binomial logistic regression analysis showed that serum sCD154 levels >1.41 ng/mmL were associated with 30-day mortality (OR = 10.25; 95% CI = 2.34–44.95; p = 0.002). Conclusions: The new more important finding of our study was that serum sCD154 levels in MMCAI patients were associated with mortality. Full article
(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)
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Review

Jump to: Research

1799 KiB  
Review
Modulating Astrocyte Transition after Stroke to Promote Brain Rescue and Functional Recovery: Emerging Targets Include Rho Kinase
by Hima Charika S. Abeysinghe, Ellie L. Phillips, Heung Chin-Cheng, Philip M. Beart and Carli L. Roulston
Int. J. Mol. Sci. 2016, 17(3), 288; https://doi.org/10.3390/ijms17030288 - 26 Feb 2016
Cited by 46 | Viewed by 9699
Abstract
Stroke is a common and serious condition, with few therapies. Whilst previous focus has been directed towards biochemical events within neurons, none have successfully prevented the progression of injury that occurs in the acute phase. New targeted treatments that promote recovery after stroke [...] Read more.
Stroke is a common and serious condition, with few therapies. Whilst previous focus has been directed towards biochemical events within neurons, none have successfully prevented the progression of injury that occurs in the acute phase. New targeted treatments that promote recovery after stroke might be a better strategy and are desperately needed for the majority of stroke survivors. Cells comprising the neurovascular unit, including blood vessels and astrocytes, present an alternative target for supporting brain rescue and recovery in the late phase of stroke, since alteration in the unit also occurs in regions outside of the lesion. One of the major changes in the unit involves extensive morphological transition of astrocytes resulting in altered energy metabolism, decreased glutamate reuptake and recycling, and retraction of astrocyte end feed from both blood vessels and neurons. Whilst globally inhibiting transitional change in astrocytes after stroke is reported to result in further damage and functional loss, we discuss the available evidence to suggest that the transitional activation of astrocytes after stroke can be modulated for improved outcomes. In particular, we review the role of Rho-kinase (ROCK) in reactive gliosis and show that inhibiting ROCK after stroke results in reduced scar formation and improved functional recovery. Full article
(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)
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411 KiB  
Review
Ischemia, Immunosuppression and Infection—Tackling the Predicaments of Post-Stroke Complications
by Raymond Shim and Connie H. Y. Wong
Int. J. Mol. Sci. 2016, 17(1), 64; https://doi.org/10.3390/ijms17010064 - 05 Jan 2016
Cited by 109 | Viewed by 9860
Abstract
The incidence of stroke has risen over the past decade and will continue to be one of the leading causes of death and disability worldwide. While a large portion of immediate death following stroke is due to cerebral infarction and neurological complications, the [...] Read more.
The incidence of stroke has risen over the past decade and will continue to be one of the leading causes of death and disability worldwide. While a large portion of immediate death following stroke is due to cerebral infarction and neurological complications, the most common medical complication in stroke patients is infection. In fact, infections, such as pneumonia and urinary tract infections, greatly worsen the clinical outcome of stroke patients. Recent evidence suggests that the disrupted interplay between the central nervous system and immune system contributes to the development of infection after stroke. The suppression of systemic immunity by the nervous system is thought to protect the brain from further inflammatory insult, yet this comes at the cost of increased susceptibility to infection after stroke. To improve patient outcome, there have been attempts to lessen the stroke-associated bacterial burden through the prophylactic use of broad-spectrum antibiotics. However, preventative antibiotic treatments have been unsuccessful, and therefore have been discouraged. Additionally, with the ever-rising obstacle of antibiotic-resistance, future therapeutic options to reverse immune impairment after stroke by augmentation of host immunity may be a viable alternative option. However, cautionary steps are required to ensure that collateral ischemic damage caused by cerebral inflammation remains minimal. Full article
(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)
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1370 KiB  
Review
Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective
by Silke Neumann, Nicholas J. Shields, Thomas Balle, Mary Chebib and Andrew N. Clarkson
Int. J. Mol. Sci. 2015, 16(12), 29029-29046; https://doi.org/10.3390/ijms161226141 - 04 Dec 2015
Cited by 46 | Viewed by 11050
Abstract
Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer’s disease, pain, Schizophrenia, and stroke. While the immune [...] Read more.
Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer’s disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR) ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells. Full article
(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)
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584 KiB  
Review
The Role of the Neuroprotective Factor Npas4 in Cerebral Ischemia
by Fong Chan Choy, Thomas S. Klarić, Simon A. Koblar and Martin D. Lewis
Int. J. Mol. Sci. 2015, 16(12), 29011-29028; https://doi.org/10.3390/ijms161226144 - 04 Dec 2015
Cited by 32 | Viewed by 8161
Abstract
Stroke is one of the leading causes of death and adult disability in the world. Although many molecules have been documented to have a neuroprotective effect, the majority of these molecules failed to improve the neurological outcomes for patients with brain ischemia. It [...] Read more.
Stroke is one of the leading causes of death and adult disability in the world. Although many molecules have been documented to have a neuroprotective effect, the majority of these molecules failed to improve the neurological outcomes for patients with brain ischemia. It has been proposed that neuroprotection alone may, in fact, not be adequate for improving the prognosis of ischemic stroke. Neuroprotectants that can regulate other processes which occur in the brain during ischemia could potentially be targets for the development of effective therapeutic interventions in stroke. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischemia. It has been shown that Npas4 plays an important role in protecting neurons against many types of neurodegenerative insult. Recently, it was demonstrated that Npas4 indeed has a neuroprotective role in ischemic stroke and that Npas4 might be involved in modulating the cell death pathway and inflammatory response. In this review, we summarize the current knowledge of the roles that Npas4 may play in neuroinflammation and ischemia. Understanding how ischemic lesion size in stroke may be reduced through modulation of Npas4-dependent apoptotic and inflammatory pathways could lead to the development of new stroke therapies. Full article
(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)
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