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1
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Al-Obaidi MMJ, Al Siyabi MSK, Muthanna A, Mohd Desa MN. Understanding the mechanisms of Streptococcus pneumoniae in penetrating the blood-brain barrier: insights into bacterial binding with central nervous system host receptors. Tissue Barriers 2024:2434764. [PMID: 39629682 DOI: 10.1080/21688370.2024.2434764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 11/12/2024] [Accepted: 11/21/2024] [Indexed: 12/13/2024] Open
Abstract
This review investigates the pathogenic processes through which Streptococcus pneumoniae crosses the blood-brain barrier (BBB) to cause meningitis, with a focus on the interaction with host receptors in the central nervous system (CNS). S. pneumoniae a primary cause of bacterial meningitis, utilizes unique receptor-mediated pathways to infiltrate the BBB. The bacterial interaction with the platelet-activating factor receptor (PAFR) and the polymeric immunoglobulin receptor (pIgR) is looked at in this study. The goal is to understand how this interaction helps the bacterium move across the BBB and cause infection in the CNS. We examine the functions of cellular and molecular participants at the endothelium level, such as cytokines, chemokines, and matrix metalloproteinases (MMP), which have a role in the development of the disease. This study consolidates data from multiple studies, providing a thorough summary of the interactions between S. pneumoniae and the BBB. It also explores potential treatment targets that could reduce the significant illness and death rates associated with pneumococcal meningitis.
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Affiliation(s)
- Mazen M Jamil Al-Obaidi
- University of Technology and Applied Sciences, Rustaq, College of Education, Science Department, Sultanate of Oman
| | - Muzna Saif Khalfan Al Siyabi
- University of Technology and Applied Sciences, College of applied sciences and pharmacy, Department of applied sciences, Biology section, Muscat, Sultanate of Oman
| | - AbdulRahman Muthanna
- Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Mohd Nasir Mohd Desa
- Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
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2
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Hendrix E, Vande Vyver M, Holt M, Smolders I. Regulatory T cells as a possible new target in epilepsy? Epilepsia 2024; 65:2227-2237. [PMID: 38888867 DOI: 10.1111/epi.18038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 05/24/2024] [Accepted: 05/29/2024] [Indexed: 06/20/2024]
Abstract
Epilepsy is a complex chronic brain disorder with diverse clinical features that can be caused by various triggering events, such as infections, head trauma, or stroke. During epileptogenesis, various abnormalities are observed, such as altered cellular homeostasis, imbalance of neurotransmitters, tissue changes, and the release of inflammatory mediators, which in combination lead to spontaneous recurrent seizures. Regulatory T cells (Tregs), a subtype of CD4+Foxp3+ T cells, best known for their key function in immune suppression, also seem to play a role in attenuating neurodegeneration and suppressing pathological inflammation in several brain disease states. Considering that epilepsy is also highly associated with neuronal damage and neuroinflammation, modulation of Tregs may be an interesting way to modify the disease course of epilepsy and needs further investigation. In this review, we will describe the currently available information on Tregs in epilepsy.
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Affiliation(s)
- Evelien Hendrix
- Department of Pharmaceutical Chemistry, Drug Analysis, and Drug Information, Research Group Experimental Pharmacology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Maxime Vande Vyver
- Department of Pharmaceutical Chemistry, Drug Analysis, and Drug Information, Research Group Experimental Pharmacology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium
- Department of Neurology and Bru-BRAIN, Universitair Ziekenhuis Brussel, Brussels, Belgium
- NEUR Research Group, Center of Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Matthew Holt
- Instituto de Investigação e Inovação Em Saúde, Porto, Portugal
| | - Ilse Smolders
- Department of Pharmaceutical Chemistry, Drug Analysis, and Drug Information, Research Group Experimental Pharmacology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium
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3
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Clement M. The association of microbial infection and adaptive immune cell activation in Alzheimer's disease. DISCOVERY IMMUNOLOGY 2023; 2:kyad015. [PMID: 38567070 PMCID: PMC10917186 DOI: 10.1093/discim/kyad015] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 07/31/2023] [Accepted: 09/04/2023] [Indexed: 04/04/2024]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Early symptoms include the loss of memory and mild cognitive ability; however, as the disease progresses, these symptoms can present with increased severity manifesting as mood and behaviour changes, disorientation, and a loss of motor/body control. AD is one of the leading causes of death in the UK, and with an ever-increasing ageing society, patient numbers are predicted to rise posing a significant global health emergency. AD is a complex neurophysiological disorder where pathology is characterized by the deposition and aggregation of misfolded amyloid-beta (Aβ)-protein that in-turn promotes excessive tau-protein production which together drives neuronal cell dysfunction, neuroinflammation, and neurodegeneration. It is widely accepted that AD is driven by a combination of both genetic and immunological processes with recent data suggesting that adaptive immune cell activity within the parenchyma occurs throughout disease. The mechanisms behind these observations remain unclear but suggest that manipulating the adaptive immune response during AD may be an effective therapeutic strategy. Using immunotherapy for AD treatment is not a new concept as the only two approved treatments for AD use antibody-based approaches to target Aβ. However, these have been shown to only temporarily ease symptoms or slow progression highlighting the urgent need for newer treatments. This review discusses the role of the adaptive immune system during AD, how microbial infections may be contributing to inflammatory immune activity and suggests how adaptive immune processes can pose as therapeutic targets for this devastating disease.
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Affiliation(s)
- Mathew Clement
- Division of Infection and Immunity, Systems Immunity University Research Institute, Cardiff University, Cardiff, UK
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4
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Chen D, Varanasi SK, Hara T, Traina K, Sun M, McDonald B, Farsakoglu Y, Clanton J, Xu S, Garcia-Rivera L, Mann TH, Du V, Chung HK, Xu Z, Tripple V, Casillas E, Ma S, O'Connor C, Yang Q, Zheng Y, Hunter T, Lemke G, Kaech SM. CTLA-4 blockade induces a microglia-Th1 cell partnership that stimulates microglia phagocytosis and anti-tumor function in glioblastoma. Immunity 2023; 56:2086-2104.e8. [PMID: 37572655 PMCID: PMC11800830 DOI: 10.1016/j.immuni.2023.07.015] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 04/14/2023] [Accepted: 07/20/2023] [Indexed: 08/14/2023]
Abstract
The limited efficacy of immunotherapies against glioblastoma underscores the urgency of better understanding immunity in the central nervous system. We found that treatment with αCTLA-4, but not αPD-1, prolonged survival in a mouse model of mesenchymal-like glioblastoma. This effect was lost upon the depletion of CD4+ T cells but not CD8+ T cells. αCTLA-4 treatment increased frequencies of intratumoral IFNγ-producing CD4+ T cells, and IFNγ blockade negated the therapeutic impact of αCTLA-4. The anti-tumor activity of CD4+ T cells did not require tumor-intrinsic MHC-II expression but rather required conventional dendritic cells as well as MHC-II expression on microglia. CD4+ T cells interacted directly with microglia, promoting IFNγ-dependent microglia activation and phagocytosis via the AXL/MER tyrosine kinase receptors, which were necessary for tumor suppression. Thus, αCTLA-4 blockade in mesenchymal-like glioblastoma promotes a CD4+ T cell-microglia circuit wherein IFNγ triggers microglia activation and phagocytosis and microglia in turn act as antigen-presenting cells fueling the CD4+ T cell response.
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Affiliation(s)
- Dan Chen
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Siva Karthik Varanasi
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Toshiro Hara
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Kacie Traina
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Ming Sun
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Bryan McDonald
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA
| | - Yagmur Farsakoglu
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Biomedicine, University of Basel, Basel 4058, Switzerland
| | - Josh Clanton
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Shihao Xu
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Lizmarie Garcia-Rivera
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA
| | - Thomas H Mann
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Victor Du
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - H Kay Chung
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Ziyan Xu
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; School of Biological Sciences, University of California, San Diego, La Jolla, CA 92037, USA
| | - Victoria Tripple
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Eduardo Casillas
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Shixin Ma
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Carolyn O'Connor
- Flow Cytometry Core Facility, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Qiyuan Yang
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Ye Zheng
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Tony Hunter
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Greg Lemke
- Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Susan M Kaech
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
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5
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Heavener KS, Bradshaw EM. The aging immune system in Alzheimer's and Parkinson's diseases. Semin Immunopathol 2022; 44:649-657. [PMID: 35505128 PMCID: PMC9519729 DOI: 10.1007/s00281-022-00944-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/20/2022] [Indexed: 11/03/2022]
Abstract
The neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) both have a myriad of risk factors including genetics, environmental exposures, and lifestyle. However, aging is the strongest risk factor for both diseases. Aging also profoundly influences the immune system, with immunosenescence perhaps the most prominent outcome. Through genetics, mouse models, and pathology, there is a growing appreciation of the role the immune system plays in neurodegenerative diseases. In this review, we explore the intersection of aging and the immune system in AD and PD.
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Affiliation(s)
- Kelsey S Heavener
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, 10032, USA
| | - Elizabeth M Bradshaw
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
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6
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Deus CM, Tavares H, Beatriz M, Mota S, Lopes C. Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders. Cells 2022; 11:2364. [PMID: 35954208 PMCID: PMC9367540 DOI: 10.3390/cells11152364] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 02/06/2023] Open
Abstract
Neuroinflammation is a common hallmark in different neurodegenerative conditions that share neuronal dysfunction and a progressive loss of a selectively vulnerable brain cell population. Alongside ageing and genetics, inflammation, oxidative stress and mitochondrial dysfunction are considered key risk factors. Microglia are considered immune sentinels of the central nervous system capable of initiating an innate and adaptive immune response. Nevertheless, the pathological mechanisms underlying the initiation and spread of inflammation in the brain are still poorly described. Recently, a new mechanism of intercellular signalling mediated by small extracellular vesicles (EVs) has been identified. EVs are nanosized particles (30-150 nm) with a bilipid membrane that carries cell-specific bioactive cargos that participate in physiological or pathological processes. Damage-associated molecular patterns (DAMPs) are cellular components recognised by the immune receptors of microglia, inducing or aggravating neuroinflammation in neurodegenerative disorders. Diverse evidence links mitochondrial dysfunction and inflammation mediated by mitochondrial-DAMPs (mtDAMPs) such as mitochondrial DNA, mitochondrial transcription factor A (TFAM) and cardiolipin, among others. Mitochondrial-derived vesicles (MDVs) are a subtype of EVs produced after mild damage to mitochondria and, upon fusion with multivesicular bodies are released as EVs to the extracellular space. MDVs are particularly enriched in mtDAMPs which can induce an immune response and the release of pro-inflammatory cytokines. Importantly, growing evidence supports the association between mitochondrial dysfunction, EV release and inflammation. Here, we describe the role of extracellular vesicles-associated mtDAMPS in physiological conditions and as neuroinflammation activators contributing to neurodegenerative disorders.
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Affiliation(s)
| | | | | | - Sandra Mota
- CNC—Center for Neuroscience and Cell Biology, CIBB—Center for Innovative Biomedicine and Biotechnology, III-Institute of Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal; (C.M.D.); (H.T.); (M.B.)
| | - Carla Lopes
- CNC—Center for Neuroscience and Cell Biology, CIBB—Center for Innovative Biomedicine and Biotechnology, III-Institute of Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal; (C.M.D.); (H.T.); (M.B.)
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7
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Yshii L, Pasciuto E, Bielefeld P, Mascali L, Lemaitre P, Marino M, Dooley J, Kouser L, Verschoren S, Lagou V, Kemps H, Gervois P, de Boer A, Burton OT, Wahis J, Verhaert J, Tareen SHK, Roca CP, Singh K, Whyte CE, Kerstens A, Callaerts-Vegh Z, Poovathingal S, Prezzemolo T, Wierda K, Dashwood A, Xie J, Van Wonterghem E, Creemers E, Aloulou M, Gsell W, Abiega O, Munck S, Vandenbroucke RE, Bronckaers A, Lemmens R, De Strooper B, Van Den Bosch L, Himmelreich U, Fitzsimons CP, Holt MG, Liston A. Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation. Nat Immunol 2022; 23:878-891. [PMID: 35618831 PMCID: PMC9174055 DOI: 10.1038/s41590-022-01208-z] [Citation(s) in RCA: 110] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/11/2022] [Indexed: 12/21/2022]
Abstract
The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune modulation and a delivery system capable of crossing the blood-brain barrier. The recent identification and characterization of a small population of regulatory T (Treg) cells resident in the brain presents one such potential therapeutic target. Here, we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident Treg cells. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected in traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL-2 gene delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.
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Affiliation(s)
- Lidia Yshii
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
| | - Emanuela Pasciuto
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
| | - Pascal Bielefeld
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
- Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
| | - Loriana Mascali
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Leuven, Belgium
| | - Pierre Lemaitre
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Leuven, Belgium
| | - Marika Marino
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
| | - James Dooley
- Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
| | - Lubna Kouser
- Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
| | - Stijn Verschoren
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
| | - Vasiliki Lagou
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Leuven, Belgium
| | - Hannelore Kemps
- Cardio & Organ Systems (COST), Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Pascal Gervois
- Cardio & Organ Systems (COST), Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Antina de Boer
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
| | - Oliver T Burton
- Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
| | - Jérôme Wahis
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
| | - Jens Verhaert
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
| | - Samar H K Tareen
- Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
| | - Carlos P Roca
- Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
| | - Kailash Singh
- Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
| | - Carly E Whyte
- Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
| | - Axelle Kerstens
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
- VIB Bio-Imaging Core, Leuven, Belgium
| | | | | | - Teresa Prezzemolo
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Leuven, Belgium
| | - Keimpe Wierda
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
- VIB-KU Leuven Center for Brain & Disease Research, Electrophysiology Expertise Unit, Leuven, Belgium
| | - Amy Dashwood
- Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
| | - Junhua Xie
- VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
| | - Elien Van Wonterghem
- VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
| | - Eline Creemers
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
- VIB-KU Leuven Center for Brain & Disease Research, Electrophysiology Expertise Unit, Leuven, Belgium
| | - Meryem Aloulou
- Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
- Toulouse Institute for Infectious and Inflammatory diseases (INFINITY), INSERM UMR1291, CNRS UMR 5051, Toulouse, France
| | - Willy Gsell
- KU Leuven, Department of Imaging and Pathology, Biomedical MRI, Leuven, Belgium
| | - Oihane Abiega
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
| | - Sebastian Munck
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
- VIB Bio-Imaging Core, Leuven, Belgium
| | - Roosmarijn E Vandenbroucke
- VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
| | - Annelies Bronckaers
- Cardio & Organ Systems (COST), Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Robin Lemmens
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
- University Hospitals Leuven, Department of Neurology, Leuven, Belgium
| | - Bart De Strooper
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
- Dementia Research Institute, University College London, London, United Kingdom
| | - Ludo Van Den Bosch
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
- KU Leuven - Department of Neurosciences, Leuven, Belgium
| | - Uwe Himmelreich
- KU Leuven, Department of Imaging and Pathology, Biomedical MRI, Leuven, Belgium
| | - Carlos P Fitzsimons
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
| | - Matthew G Holt
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
- KU Leuven - Department of Neurosciences, Leuven, Belgium.
- Instituto de Investigaçāo e Inovaçāo em Saúde (i3S), University of Porto, Porto, Portugal.
| | - Adrian Liston
- VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Leuven, Belgium.
- Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom.
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8
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Bianconi A, Aruta G, Rizzo F, Salvati LF, Zeppa P, Garbossa D, Cofano F. Systematic Review on Tumor Microenvironment in Glial Neoplasm: From Understanding Pathogenesis to Future Therapeutic Perspectives. Int J Mol Sci 2022; 23:4166. [PMID: 35456984 PMCID: PMC9029619 DOI: 10.3390/ijms23084166] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
Despite the multidisciplinary management in the treatment of glioblastomas, the average survival of GBM patients is still 15 months. In recent years, molecular biomarkers have gained more and more importance both in the diagnosis and therapy of glial tumors. At the same time, it has become clear that non neoplastic cells, which constitute about 30% of glioma mass, dramatically influence tumor growth, spread, and recurrence. This is the main reason why, in recent years, scientific research has been focused on understanding the function and the composition of tumor microenvironment and its role in gliomagenesis and recurrence. The aim of this review is to summarize the most recent discovery about resident microglia, tumor-associated macrophages, lymphocytes, and the role of extracellular vesicles and their bijective interaction with glioma cells. Moreover, we reported the most recent updates about new therapeutic strategies targeting immune system receptors and soluble factors. Understanding how glioma cells interact with non-neoplastic cells in tumor microenvironment is an essential step to comprehend mechanisms at the base of disease progression and to find new therapeutic strategies for GBM patients. However, no significant results have yet been obtained in studies targeting single molecules/pathways; considering the complex microenvironment, it is likely that only by using multiple therapeutic agents acting on multiple molecular targets can significant results be achieved.
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Affiliation(s)
- Andrea Bianconi
- Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, Italy; (G.A.); (F.R.); (P.Z.); (D.G.); (F.C.)
| | - Gelsomina Aruta
- Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, Italy; (G.A.); (F.R.); (P.Z.); (D.G.); (F.C.)
| | - Francesca Rizzo
- Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, Italy; (G.A.); (F.R.); (P.Z.); (D.G.); (F.C.)
| | | | - Pietro Zeppa
- Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, Italy; (G.A.); (F.R.); (P.Z.); (D.G.); (F.C.)
| | - Diego Garbossa
- Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, Italy; (G.A.); (F.R.); (P.Z.); (D.G.); (F.C.)
| | - Fabio Cofano
- Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, Italy; (G.A.); (F.R.); (P.Z.); (D.G.); (F.C.)
- Spine Surgery Unit, Humanitas Gradeningo, 10100 Turin, Italy
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9
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Wang L, Wei X. T Cell-Mediated Autoimmunity in Glaucoma Neurodegeneration. Front Immunol 2022; 12:803485. [PMID: 34975917 PMCID: PMC8716691 DOI: 10.3389/fimmu.2021.803485] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/01/2021] [Indexed: 02/05/2023] Open
Abstract
Glaucoma as the leading neurodegenerative disease leads to blindness in 3.6 million people aged 50 years and older worldwide. For many decades, glaucoma therapy has primarily focused on controlling intraocular pressure (IOP) and sound evidence supports its role in delaying the progress of retinal ganglial cell (RGC) damage and protecting patients from vision loss. Meanwhile, accumulating data point to the immune-mediated attack of the neural retina as the underlying pathological process behind glaucoma that may come independent of raised IOP. Recently, some scholars have suggested autoimmune aspects in glaucoma, with autoreactive T cells mediating the chief pathogenic process. This autoimmune process, as well as the pathological features of glaucoma, largely overlaps with other neurodegenerative diseases in the central nervous system (CNS), including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. In addition, immune modulation therapy, which is regarded as a potential solution for glaucoma, has been boosted in trials in some CNS neurodegenerative diseases. Thus, novel insights into the T cell-mediated immunity and treatment in CNS neurodegenerative diseases may serve as valuable inspirations for ophthalmologists. This review focuses on the role of T cell-mediated immunity in the pathogenesis of glaucoma and discusses potential applications of relevant findings of CNS neurodegenerative diseases in future glaucoma research.
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Affiliation(s)
- Lixiang Wang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Wei
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Department of Ophthalmology, Shangjin Nanfu Hospital, Chengdu, China
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10
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Zhang G, Wang Z, Hu H, Zhao M, Sun L. Microglia in Alzheimer's Disease: A Target for Therapeutic Intervention. Front Cell Neurosci 2021; 15:749587. [PMID: 34899188 PMCID: PMC8651709 DOI: 10.3389/fncel.2021.749587] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/28/2021] [Indexed: 12/31/2022] Open
Abstract
Alzheimer’s disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.
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Affiliation(s)
- Guimei Zhang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Zicheng Wang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Huiling Hu
- Department of Intensive Care Unit, The Affiliated Hospital of Qingdao University, Shandong, China
| | - Meng Zhao
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Li Sun
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
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11
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Li Y, Zhang Y, Zeng X. γδ T Cells Participating in Nervous Systems: A Story of Jekyll and Hyde. Front Immunol 2021; 12:656097. [PMID: 33868300 PMCID: PMC8044362 DOI: 10.3389/fimmu.2021.656097] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 03/15/2021] [Indexed: 11/18/2022] Open
Abstract
γδ T cells are distributed in various lymphoid and nonlymphoid tissues, and act as early responders in many conditions. Previous studies have proven their significant roles in infection, cancer, autoimmune diseases and tissue maintenance. Recently, accumulating researches have highlighted the crosstalk between γδ T cells and nervous systems. In these reports, γδ T cells maintain some physiological functions of central nervous system by secreting interleukin (IL) 17, and neurons like nociceptors can in turn regulate the activity of γδ T cells. Moreover, γδ T cells are involved in neuroinflammation such as stroke and multiple sclerosis. This review illustrates the relationship between γδ T cells and nervous systems in physiological and pathological conditions.
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Affiliation(s)
| | | | - Xun Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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12
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Bagheri-Mohammadi S. Microglia in Alzheimer's Disease: The Role of Stem Cell-Microglia Interaction in Brain Homeostasis. Neurochem Res 2021; 46:141-148. [PMID: 33174075 DOI: 10.1007/s11064-020-03162-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 09/28/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022]
Abstract
Microglia as resident cells of the brain can regulate neural development and maintenance of neuronal networks. Any types of pathologic events or changes in brain homeostasis are involved in the activation of microglia. This activation depends on the context, type of the stressor, or pathology. Due to the release of a plethora of substances such as chemokines, cytokines, and growth factors, microglia able to influence the pathologic outcome. In Alzheimer's disease (AD) condition, the deposition of amyloid-β (Aβ) result in provokes the phenotypic activation of microglia and their elaboration of pro-inflammatory molecules. New investigations reveal that cellular therapy with stem cells might have therapeutic effects in preventing the pathogenesis of AD. Although many strategies have focused on the use of stem cells to regenerate damaged neurons, new researches have demonstrated the immune-regulatory feature of stem cells which can modulate the activity state of microglia as well as mediates neuroinflammation. Hence, understanding the molecular mechanisms involved in the brain homeostasis by the protective features of mesenchymal stem cells (MSCs) could lead to remedial treatment for AD.
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Affiliation(s)
- Saeid Bagheri-Mohammadi
- Department of Physiology and Neurophysiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Physiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
- Departments of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
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13
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Kantarci A, Tognoni CM, Yaghmoor W, Marghalani A, Stephens D, Ahn JY, Carreras I, Dedeoglu A. Microglial response to experimental periodontitis in a murine model of Alzheimer's disease. Sci Rep 2020; 10:18561. [PMID: 33122702 PMCID: PMC7596239 DOI: 10.1038/s41598-020-75517-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 09/30/2020] [Indexed: 12/14/2022] Open
Abstract
Periodontal disease (PD) has been suggested to be a risk factor for Alzheimer's disease (AD). We tested the impact of ligature-induced PD on 5xFAD mice and WT littermates. At baseline, 5xFAD mice presented significant alveolar bone loss compared to WT mice. After the induction of PD, both WT and 5xFAD mice experienced alveolar bone loss. PD increased the level of Iba1-immunostained microglia in WT mice. In 5xFAD mice, PD increased the level of insoluble Aβ42. The increased level in Iba1 immunostaining that parallels the accumulation of Aβ in 5xFAD mice was not affected by PD except for a decrease in the dentate gyrus. Analysis of double-label fluorescent images showed a decline in Iba1 in the proximity of Aβ plaques in 5xFAD mice with PD compared to those without PD suggesting a PD-induced decrease in plaque-associated microglia (PAM). PD reduced IL-6, MCP-1, GM-CSF, and IFN-γ in brains of WT mice and reduced IL-10 in 5xFAD mice. The data demonstrated that PD increases neuroinflammation in WT mice and disrupts the neuroinflammatory response in 5xFAD mice and suggest that microglia is central to the association between PD and AD.
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Affiliation(s)
| | - Christina M Tognoni
- Department of Veterans Affairs, VA Boston Healthcare System, Research and Development Service, Building 1A-(151), 150 S. Huntington Avenue, Boston, MA, 02130, USA.,Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Wael Yaghmoor
- Forsyth Institute, 245 First Street, Cambridge, MA, 02142, USA
| | - Amin Marghalani
- Forsyth Institute, 245 First Street, Cambridge, MA, 02142, USA
| | | | - Jae-Yong Ahn
- Department of Veterans Affairs, VA Boston Healthcare System, Research and Development Service, Building 1A-(151), 150 S. Huntington Avenue, Boston, MA, 02130, USA.,Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Isabel Carreras
- Department of Veterans Affairs, VA Boston Healthcare System, Research and Development Service, Building 1A-(151), 150 S. Huntington Avenue, Boston, MA, 02130, USA.,Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA.,Department of Biochemistry, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Alpaslan Dedeoglu
- Department of Veterans Affairs, VA Boston Healthcare System, Research and Development Service, Building 1A-(151), 150 S. Huntington Avenue, Boston, MA, 02130, USA. .,Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA. .,Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
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14
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Uddin MS, Kabir MT, Mamun AA, Barreto GE, Rashid M, Perveen A, Ashraf GM. Pharmacological approaches to mitigate neuroinflammation in Alzheimer's disease. Int Immunopharmacol 2020; 84:106479. [PMID: 32353686 DOI: 10.1016/j.intimp.2020.106479] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 03/13/2020] [Accepted: 04/02/2020] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases characterized by the formation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Growing evidence suggested that there is an association between neuronal dysfunction and neuroinflammation (NI) in AD, coordinated by the chronic activation of astrocytes and microglial cells along with the subsequent excessive generation of the proinflammatory molecule. Therefore, a better understanding of the relationship between the nervous and immune systems is important in order to delay or avert the neurodegenerative events of AD. The inflammatory/immune pathways and the mechanisms to control these pathways may provide a novel arena to develop new drugs in order to target NI in AD. In this review, we represent the influence of cellular mediators which are involved in the NI process, with regards to the progression of AD. We also discuss the processes and the current status of multiple anti-inflammatory agents which are used in AD and have gone through or going through clinical trials. Moreover, new prospects for targeting NI in the development of AD drugs have also been highlighted.
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Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh; Pharmakon Neuroscience Research Network, Dhaka, Bangladesh.
| | | | - Abdullah Al Mamun
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh; Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - George E Barreto
- Department of Biological Sciences, University of Limerick, Limerick, Ireland; Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Mamunur Rashid
- Department of Pharmacy, University of Rajshahi, Rajshahi, Bangladesh
| | - Asma Perveen
- School of Life Sciences, The Glocal University, Saharanpur, Uttar Pradesh 247121, India
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
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15
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Guignet M, Lein PJ. Neuroinflammation in organophosphate-induced neurotoxicity. ROLE OF INFLAMMATION IN ENVIRONMENTAL NEUROTOXICITY 2019. [DOI: 10.1016/bs.ant.2018.10.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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16
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Blood‒Brain Barrier Pathology and CNS Outcomes in Streptococcus pneumoniae Meningitis. Int J Mol Sci 2018; 19:ijms19113555. [PMID: 30423890 PMCID: PMC6275034 DOI: 10.3390/ijms19113555] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/05/2018] [Accepted: 11/09/2018] [Indexed: 12/20/2022] Open
Abstract
Streptococcus pneumoniae is a major meningitis-causing pathogen globally, bringing about significant morbidity and mortality, as well as long-term neurological sequelae in almost half of the survivors. Subsequent to nasopharyngeal colonisation and systemic invasion, translocation across the blood‒brain barrier (BBB) by S. pneumoniae is a crucial early step in the pathogenesis of meningitis. The BBB, which normally protects the central nervous system (CNS) from deleterious molecules within the circulation, becomes dysfunctional in S. pneumoniae invasion due to the effects of pneumococcal toxins and a heightened host inflammatory environment of cytokines, chemokines and reactive oxygen species intracranially. The bacteria‒host interplay within the CNS likely determines not only the degree of BBB pathological changes, but also host survival and the extent of neurological damage. This review explores the relationship between S. pneumoniae bacteria and the host inflammatory response, with an emphasis on the BBB and its roles in CNS protection, as well as both the acute and long-term pathogenesis of meningitis.
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17
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Roesch S, Rapp C, Dettling S, Herold-Mende C. When Immune Cells Turn Bad-Tumor-Associated Microglia/Macrophages in Glioma. Int J Mol Sci 2018; 19:ijms19020436. [PMID: 29389898 PMCID: PMC5855658 DOI: 10.3390/ijms19020436] [Citation(s) in RCA: 225] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 12/29/2017] [Accepted: 01/29/2018] [Indexed: 12/31/2022] Open
Abstract
As a substantial part of the brain tumor microenvironment (TME), glioma-associated microglia/macrophages (GAMs) have an emerging role in tumor progression and in controlling anti-tumor immune responses. We review challenges and improvements of cell models and highlight the contribution of this highly plastic cell population to an immunosuppressive TME, besides their well-known functional role regarding glioma cell invasion and angiogenesis. Finally, we summarize first therapeutic interventions to target GAMs and their effect on the immunobiology of gliomas, focusing on their interaction with T cells.
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Affiliation(s)
- Saskia Roesch
- Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, INF400, 69120 Heidelberg, Germany.
| | - Carmen Rapp
- Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, INF400, 69120 Heidelberg, Germany.
| | - Steffen Dettling
- Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, INF400, 69120 Heidelberg, Germany.
| | - Christel Herold-Mende
- Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, INF400, 69120 Heidelberg, Germany.
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18
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O'Loughlin E, Madore C, Lassmann H, Butovsky O. Microglial Phenotypes and Functions in Multiple Sclerosis. Cold Spring Harb Perspect Med 2018; 8:8/2/a028993. [PMID: 29419406 DOI: 10.1101/cshperspect.a028993] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Microglia are the resident immune cells that constantly survey the central nervous system. They can adapt to their environment and respond to injury or insult by altering their morphology, phenotype, and functions. It has long been debated whether microglial activation is detrimental or beneficial in multiple sclerosis (MS). Recently, the two opposing yet connected roles of microglial activation have been described with the aid of novel microglial markers, RNA profiling, and in vivo models. In this review, microglial phenotypes and functions in the context of MS will be discussed with evidence from both human pathological studies, in vitro and in vivo models. Microglial functional diversity-phagocytosis, antigen presentation, immunomodulation, support, and repair-will also be examined in detail. In addition, this review discusses the emerging evidence for microglia-related targets as biomarkers and therapeutic targets for MS.
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Affiliation(s)
- Elaine O'Loughlin
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
| | - Charlotte Madore
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
| | - Hans Lassmann
- Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria
| | - Oleg Butovsky
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.,Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
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19
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Walker DJ, Spencer KA. Glucocorticoid programming of neuroimmune function. Gen Comp Endocrinol 2018; 256:80-88. [PMID: 28728884 DOI: 10.1016/j.ygcen.2017.07.016] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 07/13/2017] [Accepted: 07/16/2017] [Indexed: 01/15/2023]
Abstract
Throughout life physiological systems strive to maintain homeostasis and these systems are susceptible to exposure to maternal or environmental perturbations, particularly during embryonic development. In some cases, these perturbations may influence genetic and physiological processes that permanently alter the functioning of these physiological systems; a process known as developmental programming. In recent years, the neuroimmune system has garnered attention for its fundamental interactions with key hormonal systems, such as the hypothalamic pituitary adrenal (HPA) axis. The ultimate product of this axis, the glucocorticoid hormones, play a key role in modulating immune responses within the periphery and the CNS as part of the physiological stress response. It is well-established that elevated glucocorticoids induced by developmental stress exert profound short and long-term physiological effects, yet there is relatively little information of how these effects are manifested within the neuroimmune system. Pre and post-natal periods are prime candidates for manipulation in order to uncover the physiological mechanisms that underlie glucocorticoid programming of neuroimmune responses. Understanding the potential programming role of glucocorticoids may be key in uncovering vulnerable windows of CNS susceptibility to stressful experiences during embryonic development and improve our use of glucocorticoids as therapeutics in the treatment of neurodegenerative diseases.
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Affiliation(s)
- David J Walker
- School of Psychology & Neuroscience, University of St Andrews, Fife KY16 9JP, United Kingdom.
| | - Karen A Spencer
- School of Psychology & Neuroscience, University of St Andrews, Fife KY16 9JP, United Kingdom
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20
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Fakhoury M. Microglia and Astrocytes in Alzheimer's Disease: Implications for Therapy. Curr Neuropharmacol 2018; 16:508-518. [PMID: 28730967 PMCID: PMC5997862 DOI: 10.2174/1570159x15666170720095240] [Citation(s) in RCA: 336] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 06/21/2017] [Accepted: 07/19/2017] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the progressive loss of neurons, which typically leads to severe impairments in cognitive functions including memory and learning. Key pathological features of this disease include the deposition of highly insoluble amyloid β peptides and the formation of neurofibrillary tangles (NFTs) in the brain. Mounting evidence also implicates sustained glial-mediated inflammation as a major contributor of the neurodegenerative processes and cognitive deficits observed in AD. METHODS This paper provides an overview of findings from both human and animal studies investigating the role of microglia and astrocytes in AD, and discusses potential avenues for therapeutic intervention. RESULTS Glial-mediated inflammation is a 'double-edged sword', performing both detrimental and beneficial functions in AD. Despite tremendous effort in elucidating the molecular and cellular mechanisms underlying AD pathology, to date, there is no treatment that could prevent or cure this disease. Current treatments are only useful in slowing down the progression of AD and helping patients manage some of their behavioral and cognitive symptoms. CONCLUSION A better understanding of the role of microglia and astrocytes in the regulation of AD pathology is needed as this could pave the way for new therapeutic strategies.
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Affiliation(s)
- Marc Fakhoury
- Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
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21
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Woo J, Han D, Wang JI, Park J, Kim H, Kim Y. Quantitative Proteomics Reveals Temporal Proteomic Changes in Signaling Pathways during BV2 Mouse Microglial Cell Activation. J Proteome Res 2017; 16:3419-3432. [DOI: 10.1021/acs.jproteome.7b00445] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
| | - Dohyun Han
- Proteomics
Core Facility, Biomedical Research Institute, Seoul National University Hospital, 101 Daehangro, Seoul 110-799, Korea
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22
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Schiffer D, Mellai M, Bovio E, Annovazzi L. The neuropathological basis to the functional role of microglia/macrophages in gliomas. Neurol Sci 2017; 38:1571-1577. [PMID: 28593528 DOI: 10.1007/s10072-017-3002-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/19/2017] [Indexed: 12/19/2022]
Abstract
The paper wants to be a tracking shot of the main recent acquisitions on the function and significance of microglia/macrophages in gliomas. The observations have been principally carried out on in vitro cultures and on tumor transplants in animals. Contrary to what is deduced from microglia in non-neoplastic pathologic conditions of central nervous system (CNS), most conclusions indicate that microglia acts favoring tumor proliferation through an immunosuppression induced by glioma cells. By immunohistochemistry, different microglia phenotypes are recognized in gliomas, from ramified microglia to frank macrophagic aspect. One wonders whether the functional conclusions drawn from many microglia studies, but not in conditions of human pathology, apply to all the phenotypes recognizable in them. It is difficult to verify in human pathology a prognostic significance of microglia. Only CD163-positive microglia/macrophages inversely correlate with glioma patients' survival, whereas the total number of microglia does not change with the malignancy grade.
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Affiliation(s)
- Davide Schiffer
- Research Center, Policlinico di Monza Foundation, Via Pietro Micca 29, 13100, Vercelli, Italy.
| | - Marta Mellai
- Research Center, Policlinico di Monza Foundation, Via Pietro Micca 29, 13100, Vercelli, Italy
| | - Enrica Bovio
- Research Center, Policlinico di Monza Foundation, Via Pietro Micca 29, 13100, Vercelli, Italy
| | - Laura Annovazzi
- Research Center, Policlinico di Monza Foundation, Via Pietro Micca 29, 13100, Vercelli, Italy
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23
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Wootla B, Denic A, Watzlawik JO, Warrington AE, Zoecklein LJ, Papke-Norton LM, David C, Rodriguez M. Human class I major histocompatibility complex alleles determine central nervous system injury versus repair. J Neuroinflammation 2016; 13:293. [PMID: 27855706 PMCID: PMC5112886 DOI: 10.1186/s12974-016-0759-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 11/03/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND We investigated the role of human HLA class I molecules in persistent central nervous system (CNS) injury versus repair following virus infection of the CNS. METHODS Human class I A11+ and B27+ transgenic human beta-2 microglobulin positive (Hβ2m+) mice of the H-2 b background were generated on a combined class I-deficient (mouse beta-2 microglobulin deficient, β2m0) and class II-deficient (mouse Aβ0) phenotype. Intracranial infection with Theiler's murine encephalomyelitis virus (TMEV) in susceptible SJL mice results in acute encephalitis with prominent injury in the hippocampus, striatum, and cortex. RESULTS Following infection with TMEV, a picornavirus, the Aβ0.β2m0 mice lacking active immune responses died within 18 to 21 days post-infection. These mice showed severe encephalomyelitis due to rapid replication of the viral genome. In contrast, transgenic Hβ2m mice with insertion of a single human class I MHC gene in the absence of human or mouse class II survived the acute infection. Both A11+ and B27+ mice significantly controlled virus RNA expression by 45 days and did not develop late-onset spinal cord demyelination. By 45 days post-infection (DPI), B27+ transgenic mice showed almost complete repair of the virus-induced brain injury, but A11+ mice conversely showed persistent severe hippocampal and cortical injury. CONCLUSIONS The findings support the hypothesis that the expression of a single human class I MHC molecule, independent of persistent virus infection, influences the extent of sub frequent chronic neuronal injury or repair in the absence of a class II MHC immune response.
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Affiliation(s)
- Bharath Wootla
- Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
- Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
- Center for Regenerative Medicine, Neuroregeneration, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
| | - Aleksandar Denic
- Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
- Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
| | - Jens O. Watzlawik
- Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224 USA
| | - Arthur E. Warrington
- Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
- Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
| | - Laurie J. Zoecklein
- Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
- Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
| | - Louisa M. Papke-Norton
- Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
- Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
| | - Chella David
- Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
| | - Moses Rodriguez
- Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
- Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
- Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
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24
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Martiñón S, García-Vences E, Toscano-Tejeida D, Flores-Romero A, Rodriguez-Barrera R, Ferrusquia M, Hernández-Muñoz RE, Ibarra A. Long-term production of BDNF and NT-3 induced by A91-immunization after spinal cord injury. BMC Neurosci 2016; 17:42. [PMID: 27364353 PMCID: PMC4928355 DOI: 10.1186/s12868-016-0267-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 06/03/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND After spinal cord (SC)-injury, a non-modulated immune response contributes to the damage of neural tissue. Protective autoimmunity (PA) is a T cell mediated, neuroprotective response induced after SC-injury. Immunization with neural-derived peptides (INDP), such as A91, has shown to promote-in vitro-the production of neurotrophic factors. However, the production of these molecules has not been studied at the site of injury. RESULTS In order to evaluate these issues, we performed four experiments in adult female Sprague-Dawley rats. In the first one, brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) concentrations were evaluated at the site of lesion 21 days after SC-injury. BDNF and NT-3 were significantly increased in INDP-treated animals. In the second experiment, proliferation of anti-A91 T cells was assessed at chronic stages of injury. In this case, we found a significant proliferation of these cells in animals subjected to SC-injury + INDP. In the third experiment, we explored the amount of BDNF and NT3 at the site of injury in the chronic phase of rats subjected to either SC-contusion (SCC; moderate or severe) or SC-transection (SCT; complete or incomplete). The animals were treated with INDP immediately after injury. Rats subjected to moderate contusion or incomplete SCT showed significantly higher levels of BDNF and NT-3 as compared to PBS-immunized ones. In rats with severe SCC and complete SCT, BDNF and NT-3 concentrations were barely detected. Finally, in the fourth experiment we assessed motor function recovery in INDP-treated rats with moderate SC-injury. Rats immunized with A91 showed a significantly higher motor recovery from the first week and up to 4 months after SC-injury. CONCLUSIONS The results of this study suggest that PA boosted by immunization with A91 after moderate SC-injury can exert its benefits even at chronic stages, as shown by long-term production of BDNF and NT-3 and a substantial improvement in motor recovery.
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Affiliation(s)
- Susana Martiñón
- Facultad de Ciencias de la Salud, Centro de Investigación en Ciencias de la Salud (CICSA), Universidad Anáhuac México Norte, Huixquilucan, Estado de México, Mexico.,Centro de Investigación del Proyecto CAMINA A.C., Mexico, D.F., Mexico.,Instituto Nacional de Psiquiatría "Ramón de la Fuente Muñiz", Mexico, D.F., Mexico
| | - Elisa García-Vences
- Facultad de Ciencias de la Salud, Centro de Investigación en Ciencias de la Salud (CICSA), Universidad Anáhuac México Norte, Huixquilucan, Estado de México, Mexico
| | - Diana Toscano-Tejeida
- Facultad de Ciencias de la Salud, Centro de Investigación en Ciencias de la Salud (CICSA), Universidad Anáhuac México Norte, Huixquilucan, Estado de México, Mexico
| | - Adrian Flores-Romero
- Facultad de Ciencias de la Salud, Centro de Investigación en Ciencias de la Salud (CICSA), Universidad Anáhuac México Norte, Huixquilucan, Estado de México, Mexico
| | - Roxana Rodriguez-Barrera
- Facultad de Ciencias de la Salud, Centro de Investigación en Ciencias de la Salud (CICSA), Universidad Anáhuac México Norte, Huixquilucan, Estado de México, Mexico
| | - Manuel Ferrusquia
- Facultad de Ciencias de la Salud, Centro de Investigación en Ciencias de la Salud (CICSA), Universidad Anáhuac México Norte, Huixquilucan, Estado de México, Mexico
| | - Rolando E Hernández-Muñoz
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, UNAM, Mexico, D.F., Mexico
| | - Antonio Ibarra
- Facultad de Ciencias de la Salud, Centro de Investigación en Ciencias de la Salud (CICSA), Universidad Anáhuac México Norte, Huixquilucan, Estado de México, Mexico. .,Centro de Investigación del Proyecto CAMINA A.C., Mexico, D.F., Mexico.
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Papa S, Caron I, Rossi F, Veglianese P. Modulators of microglia: a patent review. Expert Opin Ther Pat 2016; 26:427-37. [DOI: 10.1517/13543776.2016.1135901] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Gene silencing of MCP-1 prevents microglial activation and inflammatory injury after intracerebral hemorrhage. Int Immunopharmacol 2016; 33:18-23. [PMID: 26851629 DOI: 10.1016/j.intimp.2016.01.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 01/13/2016] [Accepted: 01/15/2016] [Indexed: 12/27/2022]
Abstract
Microglia are activated after intracerebral hemorrhage and induce neuron death by releasing proinflammatory cytokines and chemokines. However, the related mechanism of microglia activation in such conditions remains elusive. MCP-1, the ligand of CCR2 expressed in the central nervous system, could promote microglia proliferation, survival and cytokine secretion. According to the previous findings, we make a hypothesis that whether alternation of MCP-1 level could attenuate microglia activation and toxicity to neuron in intracerebral hemorrhage. To identify that, we interfere with the MCP-1 expression of microglia by RNAi technology, and coculture the microglia and neuron in ICH. The results demonstrated that MCP-1 RNAi inhibited TNF-α, IL-1β and IL-6 expression in microglia and attenuated neuron injury. In conclusion, the present study suggests that MCP-1 might promote ICH induced microglia activation and toxicity to neuron, and MCP-1 RNAi might provide promising therapeutical strategy for ICH.
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27
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Dolan RT, Butler JS, O’Byrne JM, Poynton AR. Mechanical and cellular processes driving cervical myelopathy. World J Orthop 2016; 7:20-9. [PMID: 26807352 PMCID: PMC4716567 DOI: 10.5312/wjo.v7.i1.20] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Revised: 10/12/2015] [Accepted: 11/03/2015] [Indexed: 02/06/2023] Open
Abstract
Cervical myelopathy is a well-described clinical syndrome that may evolve from a combination of etiological mechanisms. It is traditionally classified by cervical spinal cord and/or nerve root compression which varies in severity and number of levels involved. The vast array of clinical manifestations of cervical myelopathy cannot fully be explained by the simple concept that a narrowed spinal canal causes compression of the cord, local tissue ischemia, injury and neurological impairment. Despite advances in surgical technology and treatment innovations, there are limited neuro-protective treatments for cervical myelopathy, which reflects an incomplete understanding of the pathophysiological processes involved in this disease. The aim of this review is to provide a comprehensive overview of the key pathophysiological processes at play in the development of cervical myelopathy.
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Toben C, Baune BT. An Act of Balance Between Adaptive and Maladaptive Immunity in Depression: a Role for T Lymphocytes. J Neuroimmune Pharmacol 2015; 10:595-609. [PMID: 26133121 DOI: 10.1007/s11481-015-9620-2] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 06/19/2015] [Indexed: 12/25/2022]
Abstract
Historically the monoaminergic neurotransmitter system, in particular the serotonergic system, was seen as being responsible for the pathophysiology of major depressive disorder (MDD). With the advent of psychoneuroimmunology an important role of the immune system in the interface between the central nervous systems (CNS) and peripheral organ systems has emerged. In addition to the well-characterised neurobiological activities of cytokines, T cell function in the context of depression has been neglected so far. In this review we will investigate the biological roles of T cells in depression. Originally it was thought that the adaptive immune arm including T lymphocytes was excluded from the CNS. It is now clear that peripheral naïve T cells not only carry out continuous surveillance within the brain but also maintain neural plasticity. Furthermore animal studies demonstrate that regulatory T lymphocytes can provide protection against maladaptive behavioural responses associated with depression. Psychogenic stress as a major inducer of depression can lead to transient trafficking of T lymphocytes into the brain stimulating the secretion of certain neurotrophic factors and cytokines. The separate and combined mechanism of CD4 and CD8 T cell activation is likely to determine the response pattern of CNS specific neurokines and neurotrophins. Under chronic stress-induced neuroinflammatory conditions associated with depression, T cell responses may become maladaptive and can be involved in neurodegeneration. Additionally, intracellular adhesion and MHC molecule expression as well as glucocorticoid receptor expression within the brain may play a role in determining T lymphocyte functionality in depression. Taken together, T lymphocyte mechanisms, which confer susceptibility or resilience to MDD, are not yet fully understood. Further insight into the cellular and molecular mechanisms which balance the adaptive and maladaptive roles of T lymphocytes may provide a better understanding of both the neuro- degenerative and -regenerative repair functions as present within the neuroimmune network during depression. Furthermore T cells may be important players in restoration of normal behaviour and immune cell homeostasis in depression.
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Affiliation(s)
- Catherine Toben
- Discipline of Psychiatry, University of Adelaide, 5005, Adelaide, SA, Australia
| | - Bernhard T Baune
- Discipline of Psychiatry, University of Adelaide, 5005, Adelaide, SA, Australia.
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29
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Jorfi M, Skousen JL, Weder C, Capadona JR. Progress towards biocompatible intracortical microelectrodes for neural interfacing applications. J Neural Eng 2014; 12:011001. [PMID: 25460808 DOI: 10.1088/1741-2560/12/1/011001] [Citation(s) in RCA: 231] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
To ensure long-term consistent neural recordings, next-generation intracortical microelectrodes are being developed with an increased emphasis on reducing the neuro-inflammatory response. The increased emphasis stems from the improved understanding of the multifaceted role that inflammation may play in disrupting both biologic and abiologic components of the overall neural interface circuit. To combat neuro-inflammation and improve recording quality, the field is actively progressing from traditional inorganic materials towards approaches that either minimizes the microelectrode footprint or that incorporate compliant materials, bioactive molecules, conducting polymers or nanomaterials. However, the immune-privileged cortical tissue introduces an added complexity compared to other biomedical applications that remains to be fully understood. This review provides a comprehensive reflection on the current understanding of the key failure modes that may impact intracortical microelectrode performance. In addition, a detailed overview of the current status of various materials-based approaches that have gained interest for neural interfacing applications is presented, and key challenges that remain to be overcome are discussed. Finally, we present our vision on the future directions of materials-based treatments to improve intracortical microelectrodes for neural interfacing.
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Affiliation(s)
- Mehdi Jorfi
- Adolphe Merkle Institute, University of Fribourg, Rte de l'Ancienne Papeterie, CH-1723 Marly, Switzerland
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30
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Gao Z, Nissen JC, Ji K, Tsirka SE. The experimental autoimmune encephalomyelitis disease course is modulated by nicotine and other cigarette smoke components. PLoS One 2014; 9:e107979. [PMID: 25250777 PMCID: PMC4176721 DOI: 10.1371/journal.pone.0107979] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 08/16/2014] [Indexed: 12/12/2022] Open
Abstract
Epidemiological studies have reported that cigarette smoking increases the risk of developing multiple sclerosis (MS) and accelerates its progression. However, the molecular mechanisms underlying these effects remain unsettled. We have investigated here the effects of the nicotine and the non-nicotine components in cigarette smoke on MS using the experimental autoimmune encephalomyelitis (EAE) model, and have explored their underlying mechanism of action. Our results show that nicotine ameliorates the severity of EAE, as shown by reduced demyelination, increased body weight, and attenuated microglial activation. Nicotine administration after the development of EAE symptoms prevented further disease exacerbation, suggesting that it might be useful as an EAE/MS therapeutic. In contrast, the remaining components of cigarette smoke, delivered as cigarette smoke condensate (CSC), accelerated and increased adverse clinical symptoms during the early stages of EAE, and we identify a particular cigarette smoke compound, acrolein, as one of the potential mediators. We also show that the mechanisms underlying the opposing effects of nicotine and CSC on EAE are likely due to distinct effects on microglial viability, activation, and function.
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Affiliation(s)
- Zhen Gao
- Department of Pharmacological Sciences, School of Medicine, Stony Brook University, Stony Brook, New York, United States of America
- Program in Neuroscience, School of Medicine, Stony Brook University, Stony Brook, New York, United States of America
| | - Jillian C. Nissen
- Department of Pharmacological Sciences, School of Medicine, Stony Brook University, Stony Brook, New York, United States of America
| | - Kyungmin Ji
- Department of Pharmacological Sciences, School of Medicine, Stony Brook University, Stony Brook, New York, United States of America
| | - Stella E. Tsirka
- Department of Pharmacological Sciences, School of Medicine, Stony Brook University, Stony Brook, New York, United States of America
- Program in Neuroscience, School of Medicine, Stony Brook University, Stony Brook, New York, United States of America
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31
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Song J, Cheon SY, Jung W, Lee WT, Lee JE. Resveratrol induces the expression of interleukin-10 and brain-derived neurotrophic factor in BV2 microglia under hypoxia. Int J Mol Sci 2014; 15:15512-15529. [PMID: 25184950 PMCID: PMC4200860 DOI: 10.3390/ijms150915512] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 08/08/2014] [Accepted: 08/26/2014] [Indexed: 11/26/2022] Open
Abstract
Microglia are the resident macrophages of the central nervous system (CNS) and play an important role in neuronal recovery by scavenging damaged neurons. However, overactivation of microglia leads to neuronal death that is associated with CNS disorders. Therefore, regulation of microglial activation has been suggested to be an important target for treatment of CNS diseases. In the present study, we investigated the beneficial effect of resveratrol, a natural phenol with antioxidant effects, in the microglial cell line, BV2, in a model of hypoxia injury. Resveratrol suppressed the mRNA expression of the pro-inflammatory molecule, tumor necrosis factor-α, and promoted the mRNA expression of the anti-inflammatory molecule, interleukin-10, in BV2 microglia under hypoxic conditions. In addition, resveratrol inhibited the activation of the transcription factor, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), which is upstream in the control of inflammatory reactions in hypoxia-injured BV2 microglia. Moreover, resveratrol promoted the expression of brain-derived neurotrophic factor (BDNF) in BV2 microglia under hypoxic stress. Overall, resveratrol may promote the beneficial function of microglia in ischemic brain injury.
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Affiliation(s)
- Juhyun Song
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea.
| | - So Yeong Cheon
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea.
| | - Wonsug Jung
- Department of Anatomy, Gachon University School of Medicine, Incheon 406-799, Korea.
| | - Won Taek Lee
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea.
| | - Jong Eun Lee
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea.
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32
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Jones TB. Lymphocytes and autoimmunity after spinal cord injury. Exp Neurol 2014; 258:78-90. [PMID: 25017889 DOI: 10.1016/j.expneurol.2014.03.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Revised: 03/05/2014] [Accepted: 03/06/2014] [Indexed: 12/23/2022]
Abstract
Over the past 15 years an immense amount of data has accumulated regarding the infiltration and activation of lymphocytes in the traumatized spinal cord. Although the impact of the intraspinal accumulation of lymphocytes is still unclear, modulation of the adaptive immune response via active and passive vaccination is being evaluated for its preclinical efficacy in improving the outcome for spinal-injured individuals. The complexity of the interaction between the nervous and the immune systems is highlighted in the contradictions that appear in response to these modulations. Current evidence regarding augmentation and inhibition of the adaptive immune response to spinal cord injury is reviewed with an aim toward reconciling conflicting data and providing consensus issues that may be exploited in future therapies. Opportunities such an approach may provide are highlighted as well as the obstacles that must be overcome before such approaches can be translated into clinical trials.
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Affiliation(s)
- T Bucky Jones
- Department of Anatomy, Arizona College of Medicine, Midwestern University, Glendale, AZ, USA.
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Giunti D, Parodi B, Cordano C, Uccelli A, Kerlero de Rosbo N. Can we switch microglia's phenotype to foster neuroprotection? Focus on multiple sclerosis. Immunology 2014; 141:328-39. [PMID: 24116890 DOI: 10.1111/imm.12177] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 09/30/2013] [Indexed: 12/17/2022] Open
Abstract
Microglia cells, the resident innate immune cells in the brain, are highly active, extending and retracting highly motile processes through which they continuously survey their microenvironment for 'danger signals' and interact dynamically with surrounding cells. Upon sensing changes in their central nervous system microenvironment, microglia become activated, undergoing morphological and functional changes. Microglia activation is not an 'all-or-none' process, but rather a continuum depending on encountered stimuli, which is expressed through a spectrum of molecular and functional phenotypes ranging from so-called 'classically activated', with a highly pro-inflammatory profile, to 'alternatively activated' associated with a beneficial, less inflammatory, neuroprotective profile. Microglia activation has been demonstrated in most neurological diseases of diverse aetiology and has been implicated as a contributor to neurodegeneration. The possibility to promote microglia's neuroprotective phenotype has therefore become a therapeutic goal. We have focused our discussion on the role of microglia in multiple sclerosis, a prototype of inflammatory, demyelinating, neurodegenerative disease, and on the effect of currently approved or on-trial anti-inflammatory therapeutic strategies that might mediate neuroprotection at least in part through their effect on microglia by modifying their behaviour via a switch of their functional phenotype from a detrimental to a protective one. In addition to pharmaceutical approaches, such as treatment with glatiramer acetate, interferon-β, fingolimod or dimethyl fumarate, we address the alternative therapeutic approach of treatment with mesenchymal stem cells and their potential role in neuroprotection through their 'calming' effect on microglia.
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Affiliation(s)
- Debora Giunti
- Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation and Child Health, University of Genoa, Genoa, Italy
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Boido M, Piras A, Valsecchi V, Spigolon G, Mareschi K, Ferrero I, Vizzini A, Temi S, Mazzini L, Fagioli F, Vercelli A. Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis. Cytotherapy 2014; 16:1059-72. [PMID: 24794182 DOI: 10.1016/j.jcyt.2014.02.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 02/03/2014] [Accepted: 02/09/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs), after intraparenchymal, intrathecal and endovenous administration, have been previously tested for cell therapy in amyotrophic lateral sclerosis in the SOD1 (superoxide dismutase 1) mouse. However, every administration route has specific pros and cons. METHODS We administrated human MSCs (hMSCs) in the cisterna lumbaris, which is easily accessible and could be used in outpatient surgery, in the SOD1 G93A mouse, at the earliest onset of symptoms. Control animals received saline injections. Motor behavior was checked starting from 2 months of age until the mice were killed. Animals were killed 2 weeks after transplantation; lumbar motoneurons were stereologically counted, astrocytes and microglia were analyzed and quantified after immunohistochemistry and cytokine expression was assayed by means of real-time polymerase chain reaction. RESULTS We provide evidence that this route of administration can exert strongly positive effects. Motoneuron death and motor decay were delayed, astrogliosis was reduced and microglial activation was modulated. In addition, hMSC transplantation prevented the downregulation of the anti-inflammatory interleukin-10, as well as that of vascular endothelial growth factor observed in saline-treated transgenic mice compared with wild type, and resulted in a dramatic increase in the expression of the anti-inflammatory interleukin-13. CONCLUSIONS Our results suggest that hMSCs, when intracisternally administered, can exert their paracrine potential, influencing the inflammatory response of the host.
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Affiliation(s)
- Marina Boido
- Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Torino, Italy.
| | - Antonio Piras
- Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Torino, Italy
| | - Valeria Valsecchi
- Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Torino, Italy
| | - Giada Spigolon
- Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Torino, Italy
| | - Katia Mareschi
- Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, City of Science and Health of Turin, Regina Margherita Children's Hospital, Department of Public Health and Paediatrics, University of Torino, Torino, Italy
| | - Ivana Ferrero
- Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, City of Science and Health of Turin, Regina Margherita Children's Hospital, Department of Public Health and Paediatrics, University of Torino, Torino, Italy
| | - Andrea Vizzini
- Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Torino, Italy
| | - Santa Temi
- Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Torino, Italy
| | - Letizia Mazzini
- ALS Centre Department of Neurology, University of Eastern Piedmont, Novara, Italy
| | - Franca Fagioli
- Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, City of Science and Health of Turin, Regina Margherita Children's Hospital, Department of Public Health and Paediatrics, University of Torino, Torino, Italy
| | - Alessandro Vercelli
- Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Torino, Italy
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Wu HM, Zhang LF, Ding PS, Liu YJ, Wu X, Zhou JN. Microglial activation mediates host neuronal survival induced by neural stem cells. J Cell Mol Med 2014; 18:1300-12. [PMID: 24725889 PMCID: PMC4124015 DOI: 10.1111/jcmm.12281] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 02/12/2014] [Indexed: 12/19/2022] Open
Abstract
The rational of neural stem cells (NSCs) in the therapy of neurological disease is either to replace dead neurons or to improve host neuronal survival, the latter of which has got less attention and the underlying mechanism is as yet little known. Using a transwell co-culture system, we reported that, in organotypic brain slice cultures, NSCs significantly improved host neuronal viability. Interestingly, this beneficial effect of NSCs was abrogated by a microglial inhibitor minocycline, while it was mimicked by a microglial agonist, Toll-like receptor 9 (TLR9) ligand CpG-ODN, which supports the pro-vital mediation by microglia on this NSCs-improved neuronal survival. Moreover, we showed that NSCs significantly induced host microglial movement and higher expression of a microglial marker IBA-1, the latter of which was positively correlated with TLR9 or extracellular-regulated protein kinases 1/2 (ERK1/2) activation. Real-time PCR revealed that NSCs inhibited the expression of pro-inflammatory molecules, but significantly increased the expression of molecules associated with a neuroprotective phenotype such as CX3CR1, triggering receptor expressed on myeloid cells-2 (TREM2) and insulin growth factor 1 (IGF-1). Similarly, in the microglia cells, NSCs induced the same microglial response as that in the slices. Further treatment with TLR9 ligand CpG-ODN, TLR9 inhibitor chloroquine (CQ) or ERK1/2 inhibitor U0126 demonstrated that TLR9-ERK1/2 pathway was involved in the NSCs-induced microglial activation. Collectively, this study indicated that NSCs improve host neuronal survival by switching microglia from a detrimental to a neuroprotective phenotype in adult mouse brain, and the microglial TLR9-ERK1/2 pathway seems to participate in this NSCs-mediated rescue action.
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Affiliation(s)
- Hui-Mei Wu
- CAS Key Laboratory of Brain Function and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui, China; Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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36
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Jensen SK, Yong VW. Microglial modulation as a mechanism behind the promotion of central nervous system well-being by physical exercise. ACTA ACUST UNITED AC 2014. [DOI: 10.1111/cen3.12093] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Samuel K. Jensen
- Hotchkiss Brain Institute and the Department of Clinical Neurosciences; University of Calgary; Calgary AB Canada
| | - V. Wee Yong
- Hotchkiss Brain Institute and the Department of Clinical Neurosciences; University of Calgary; Calgary AB Canada
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Autologous cord blood therapy for infantile cerebral palsy: from bench to bedside. Obstet Gynecol Int 2014; 2014:976321. [PMID: 24695413 PMCID: PMC3956288 DOI: 10.1155/2014/976321] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 12/28/2013] [Indexed: 01/19/2023] Open
Abstract
About 17 million people worldwide live with cerebral palsy, the most common disability in childhood, with hypoxic-ischemic encephalopathy, preterm birth, and low birth weight being the most important risk factors. This review will focus on recent developments in cell therapy for infantile cerebral palsy by transplantation of autologous umbilical cord blood. There are only 4 publications available at present; however, the observations made along with experimental data in vivo and in vitro may be of utmost importance clinically, so that a review at an early developmental stage of this new therapeutic concept seems justified. Particularly, since the first published double-blind randomized placebo-controlled trial in a paradigm using allogeneic cord blood and erythropoietin to treat cerebral palsy under immunosuppression showed beneficial therapeutic effects in infantile cerebral palsy, long-held doubts about the efficacy of this new cell therapy are dispelled and a revision of therapeutic views upon an ailment, for which there is no cure at present, is warranted. Hence, this review will summarize the available information on autologous cord blood therapy for cerebral palsy and that on the relevant experimental work as far as potential mechanisms and modes of action are concerned.
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Rivers-Auty J, Ashton JC. Neuroinflammation in ischemic brain injury as an adaptive process. Med Hypotheses 2013; 82:151-8. [PMID: 24345344 DOI: 10.1016/j.mehy.2013.11.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 11/12/2013] [Accepted: 11/19/2013] [Indexed: 12/12/2022]
Abstract
Cerebral ischaemia triggers various physiological processes, some of which have been considered deleterious and others beneficial. These processes have been characterized in one influential model as being part of a transition from injury to repair processes. We argue that another important distinction is between dysregulated and regulated processes. Although intervening in the course of dysregulated processes may be neuroprotective, this is unlikely to be true for regulated processes. This is because from an evolutionary perspective, regulated complex processes that are conserved across many species are likely to be adaptive and provide a survival advantage. We argue that the neuroinflammatory cascade is an adaptive process in this sense, and contrast this with a currently popular theory which we term the maladaptive immune response theory. We review the evidence from clinical and preclinical pharmacology with respect to this theory, and deduced that the evidence is inconclusive at best, and probably falsifies the theory. We argue that this is why there are no anti-inflammatory treatments for cerebral ischaemia, despite 30 years of seemingly promising preclinical results. We therefore propose an opposing theory, which we call the adaptive immune response hypothesis.
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Affiliation(s)
- Jack Rivers-Auty
- Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, P.O. Box 913, Dunedin, New Zealand
| | - John C Ashton
- Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, P.O. Box 913, Dunedin, New Zealand.
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39
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Silva NA, Sousa N, Reis RL, Salgado AJ. From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol 2013; 114:25-57. [PMID: 24269804 DOI: 10.1016/j.pneurobio.2013.11.002] [Citation(s) in RCA: 555] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Revised: 11/12/2013] [Accepted: 11/12/2013] [Indexed: 12/15/2022]
Abstract
Spinal cord injury (SCI) is a devastating neurological disorder that affects thousands of individuals each year. Over the past decades an enormous progress has been made in our understanding of the molecular and cellular events generated by SCI, providing insights into crucial mechanisms that contribute to tissue damage and regenerative failure of injured neurons. Current treatment options for SCI include the use of high dose methylprednisolone, surgical interventions to stabilize and decompress the spinal cord, and rehabilitative care. Nonetheless, SCI is still a harmful condition for which there is yet no cure. Cellular, molecular, rehabilitative training and combinatorial therapies have shown promising results in animal models. Nevertheless, work remains to be done to ascertain whether any of these therapies can safely improve patient's condition after human SCI. This review provides an extensive overview of SCI research, as well as its clinical component. It starts covering areas from physiology and anatomy of the spinal cord, neuropathology of the SCI, current clinical options, neuronal plasticity after SCI, animal models and techniques to assess recovery, focusing the subsequent discussion on a variety of promising neuroprotective, cell-based and combinatorial therapeutic approaches that have recently moved, or are close, to clinical testing.
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Affiliation(s)
- Nuno A Silva
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rui L Reis
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal; 3B's Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, 4806-909 Caldas das Taipas, Guimarães, Portugal
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
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40
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Jha MK, Seo M, Kim JH, Kim BG, Cho JY, Suk K. The secretome signature of reactive glial cells and its pathological implications. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2013; 1834:2418-28. [PMID: 23269363 DOI: 10.1016/j.bbapap.2012.12.006] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 11/23/2012] [Accepted: 12/12/2012] [Indexed: 12/12/2022]
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41
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Qian S, Tang Y, Cheng L, Sun X, Tian J, Zhou C. Interaction of copolymer-1-activated T cells and microglia in retinal ganglion cell protection. Clin Exp Ophthalmol 2013; 41:881-90. [PMID: 23566072 DOI: 10.1111/ceo.12110] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2012] [Accepted: 03/14/2013] [Indexed: 12/14/2022]
Affiliation(s)
- Shaohong Qian
- Department of Ophthalmology; EENT Hospital of Fudan University; Shanghai China
| | - Yating Tang
- Department of Ophthalmology; EENT Hospital of Fudan University; Shanghai China
| | - Lina Cheng
- Department of Ophthalmology; no. 2 Hospital of Xi'an; Shanxi China
| | - Xinghuai Sun
- Department of Ophthalmology; EENT Hospital of Fudan University; Shanghai China
| | - Jie Tian
- Central Lab; EENT Hospital of Fudan University; Shanghai China
| | - Chuandi Zhou
- Department of Ophthalmology; EENT Hospital of Fudan University; Shanghai China
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42
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London A, Cohen M, Schwartz M. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front Cell Neurosci 2013; 7:34. [PMID: 23596391 PMCID: PMC3625831 DOI: 10.3389/fncel.2013.00034] [Citation(s) in RCA: 213] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 03/18/2013] [Indexed: 11/25/2022] Open
Abstract
Functional macrophage heterogeneity is recognized outside the central nervous system (CNS), where alternatively activated macrophages can perform immune-resolving functions. Such functional heterogeneity was largely ignored in the CNS, with respect to the resident microglia and the myeloid-derived cells recruited from the blood following injury or disease, previously defined as blood-derived microglia; both were indistinguishably perceived detrimental. Our studies have led us to view the myeloid-derived infiltrating cells as functionally distinct from the resident microglia, and accordingly, to name them monocyte-derived macrophages (mo-MΦ). Although microglia perform various maintenance and protective roles, under certain conditions when they can no longer provide protection, mo-MΦ are recruited to the damaged CNS; there, they act not as microglial replacements but rather assistant cells, providing activities that cannot be timely performed by the resident cells. Here, we focus on the functional heterogeneity of microglia/mo-MΦ, emphasizing that, as opposed to the mo-MΦ, microglia often fail to timely acquire the phenotype essential for CNS repair.
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Affiliation(s)
- Anat London
- Department of Neurobiology, Weizmann Institute of Science Rehovot, Israel
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43
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Eisenkraft A, Falk A, Finkelstein A. The role of glutamate and the immune system in organophosphate-induced CNS damage. Neurotox Res 2013; 24:265-79. [PMID: 23532600 DOI: 10.1007/s12640-013-9388-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 03/10/2013] [Accepted: 03/15/2013] [Indexed: 12/12/2022]
Abstract
Organophosphate (OP) poisoning is associated with long-lasting neurological damage, which is attributed mainly to the excessive levels of glutamate caused by the intoxication. Glutamate toxicity, however, is not specific to OP poisoning, and is linked to propagation of damage in both acute and chronic neurodegenerative conditions in the central nervous system (CNS). In addition to acute excitotoxic effects of glutamate, there is now a growing amount of evidence of its intricate immunomodulatory effects in the brain, involving both the innate and the adaptive immune systems. Moreover, it was demonstrated that immunomodulatory treatments, aimed at regulating the interaction between the resident immune cells of the brain (microglia) and the peripheral immune system, can support buffering of excessive levels of glutamate and restoration of the homeostasis. In this review, we will discuss the role of glutamate as an excitotoxic agent in the acute phase of OP poisoning, and the possible functions it may have as both a neuroprotectant and an immunomodulator in the sub-acute and chronic phases of OP poisoning. In addition, we will describe the novel immune-based neuroprotective strategies aimed at counteracting the long-term neurodegenerative effects of glutamate in the CNS.
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44
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Kalsi-Ryan S, Karadimas SK, Fehlings MG. Cervical spondylotic myelopathy: the clinical phenomenon and the current pathobiology of an increasingly prevalent and devastating disorder. Neuroscientist 2012. [PMID: 23204243 DOI: 10.1177/1073858412467377] [Citation(s) in RCA: 282] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cervical spondylotic myelopathy (CSM) is a common disorder involving chronic progressive compression of the cervical spinal cord due to degenerative disc disease, spondylosis, or other degenerative pathology. CSM is the most common form of spinal cord impairment and causes functional decline leading to reduced independence and quality of life. Despite a sound understanding of the disease process, clinical presentation and management, a universal definition of CSM and a standardized index of severity are not currently used universally. Work is required to develop a definition and establish clinical predictors of progression to improve management of CSM. Despite advances in decompressive and reconstructive surgery, patients are often left with residual disability. Gaps in knowledge of the pathobiology of CSM have limited therapeutic advances to complement surgery. Although the histopathologic and pathophysiologic similarities between CSM and traumatic spinal cord injury have long been acknowledged, the unique pathomechanisms of CSM remain unexplored. Increased efforts to elucidate CSM pathobiology could lead to the discovery of novel therapeutic targets for human CSM and other spinal cord diseases. Here, the natural history of CSM, epidemiology, clinical presentation, and current methods of clinical management are reported, along with the current state of basic scientific research in the field.
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45
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Wasielewski B, Jensen A, Roth-Härer A, Dermietzel R, Meier C. Neuroglial activation and Cx43 expression are reduced upon transplantation of human umbilical cord blood cells after perinatal hypoxic-ischemic injury. Brain Res 2012; 1487:39-53. [PMID: 22796290 DOI: 10.1016/j.brainres.2012.05.066] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2012] [Accepted: 05/31/2012] [Indexed: 12/15/2022]
Abstract
Glial cells play a crucial role in the pathomechanism of perinatal hypoxic-ischemic brain injury (HI) and are involved in the maintenance of a chronic state of inflammation that causes delayed neuronal damage. Activation of astrocytes is one factor prolonging brain damage and contributing to the formation of a glial scar that limits neuronal plasticity. In this context, the major astrocytic gap junction protein Connexin 43 (Cx43) has been ascribed various functions including regulation of astrocytic migration and proliferation. Here, we investigate glial responses like microglia/macrophages and astrocytic activation in a rat model of neonatal HI and characterize changes of these parameters upon transplantation of human umbilical cord blood cells (hUCB). As an alleviation of motor function in lesioned rats has previously been described in transplanted animals, we analyze the putative correlation between motor function and glial activation over time. The lesion-induced impairment of motor function, assessed by forelimb use bias, muscle strength and distal spasticity, was alleviated upon transplantation of hUCB short and long term. HI induced an acute inflammatory reaction with activation of microglia/macrophages and reactive astrogliosis associated with perilesional upregulation of Cx43 that slowly declined during the chronic post-ischemic phase. hUCB transplantation accelerated the regression of inflammatory events, narrowed the perilesional astrocytic wall and led to a downregulation of the investigated astrocytic proteins. Thus, in the immature brain, hUCB may indirectly reduce secondary cell death upon hypoxia-ischemia and facilitate post-ischemic plasticity through the attenuation of reactive gliosis. This article is part of a Special Issue entitled Electrical Synapses.
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Affiliation(s)
- Bianca Wasielewski
- Department of Neuroanatomy and Molecular Brain Research, Ruhr-University Bochum, D-44801 Bochum, Germany
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46
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Luo XG, Chen SD. The changing phenotype of microglia from homeostasis to disease. Transl Neurodegener 2012; 1:9. [PMID: 23210447 PMCID: PMC3514090 DOI: 10.1186/2047-9158-1-9] [Citation(s) in RCA: 167] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2012] [Accepted: 04/24/2012] [Indexed: 12/20/2022] Open
Abstract
It has been nearly a century since the early description of microglia by Rio-Hortega; since then many more biological and pathological features of microglia have been recognized. Today, microglia are generally considered to be beneficial to homeostasis at the resting state through their abilities to survey the environment and phagocytose debris. However, when activated microglia assume diverse phenotypes ranging from fully inflamed, which involves the release of many pro-inflammatory cytokines, to alternatively activated, releasing anti-inflammatory cytokines or neurotrophins, the consequences to neurons can range from detrimental to supportive. Due to the different experimental sets and conditions, contradictory results have been obtained regarding the controversial question of whether microglia are “good” or “bad.” While it is well understood that the dual roles of activated microglia depend on specific situations, the underlying mechanisms have remained largely unclear, and the interpretation of certain findings related to diverse microglial phenotypes continues to be problematic. In this review we discuss the functions of microglia in neuronal survival and neurogenesis, the crosstalk between microglia and surrounding cells, and the potential factors that could influence the eventual manifestation of microglia.
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Affiliation(s)
- Xiao-Guang Luo
- Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University, Shanghai, 200025, China.
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47
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Development of protective autoimmunity by immunization with a neural-derived peptide is ineffective in severe spinal cord injury. PLoS One 2012; 7:e32027. [PMID: 22348141 PMCID: PMC3279414 DOI: 10.1371/journal.pone.0032027] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2011] [Accepted: 01/17/2012] [Indexed: 11/19/2022] Open
Abstract
Protective autoimmunity (PA) is a physiological response to central nervous system trauma that has demonstrated to promote neuroprotection after spinal cord injury (SCI). To reach its beneficial effect, PA should be boosted by immunizing with neural constituents or neural-derived peptides such as A91. Immunizing with A91 has shown to promote neuroprotection after SCI and its use has proven to be feasible in a clinical setting. The broad applications of neural-derived peptides make it important to determine the main features of this anti-A91 response. For this purpose, adult Sprague-Dawley rats were subjected to a spinal cord contusion (SCC; moderate or severe) or a spinal cord transection (SCT; complete or incomplete). Immediately after injury, animals were immunized with PBS or A91. Motor recovery, T cell-specific response against A91 and the levels of IL-4, IFN-γ and brain-derived neurotrophic factor (BDNF) released by A91-specific T (TA91) cells were evaluated. Rats with moderate SCC, presented a better motor recovery after A91 immunization. Animals with moderate SCC or incomplete SCT showed significant T cell proliferation against A91 that was characterized chiefly by the predominant production of IL-4 and the release of BDNF. In contrast, immunization with A91 did not promote a better motor recovery in animals with severe SCC or complete SCT. In fact, T cell proliferation against A91 was diminished in these animals. The present results suggest that the effective development of PA and, consequently, the beneficial effects of immunizing with A91 significantly depend on the severity of SCI. This could mainly be attributed to the lack of TA91 cells which predominantly showed to have a Th2 phenotype capable of producing BDNF, further promoting neuroprotection.
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Finkelstein A, Kunis G, Berkutzki T, Ronen A, Krivoy A, Yoles E, Last D, Mardor Y, Van Shura K, McFarland E, Capacio BA, Eisner C, Gonzales M, Gregorowicz D, Eisenkraft A, McDonough JH, Schwartz M. Immunomodulation by poly-YE reduces organophosphate-induced brain damage. Brain Behav Immun 2012; 26:159-69. [PMID: 21925261 DOI: 10.1016/j.bbi.2011.09.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Accepted: 09/01/2011] [Indexed: 10/17/2022] Open
Abstract
Accidental organophosphate poisoning resulting from environmental or occupational exposure, as well as the deliberate use of nerve agents on the battlefield or by terrorists, remain major threats for multi-casualty events, with no effective therapies yet available. Even transient exposure to organophosphorous compounds may lead to brain damage associated with microglial activation and to long-lasting neurological and psychological deficits. Regulation of the microglial response by adaptive immunity was previously shown to reduce the consequences of acute insult to the central nervous system (CNS). Here, we tested whether an immunization-based treatment that affects the properties of T regulatory cells (Tregs) can reduce brain damage following organophosphate intoxication, as a supplement to the standard antidotal protocol. Rats were intoxicated by acute exposure to the nerve agent soman, or the organophosphate pesticide, paraoxon, and after 24 h were treated with the immunomodulator, poly-YE. A single injection of poly-YE resulted in a significant increase in neuronal survival and tissue preservation. The beneficial effect of poly-YE treatment was associated with specific recruitment of CD4(+) T cells into the brain, reduced microglial activation, and an increase in the levels of brain derived neurotrophic factor (BDNF) in the piriform cortex. These results suggest therapeutic intervention with poly-YE as an immunomodulatory supplementary approach against consequences of organophosphate-induced brain damage.
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Affiliation(s)
- Arseny Finkelstein
- Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel
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Animal Models of MS Reveal Multiple Roles of Microglia in Disease Pathogenesis. Neurol Res Int 2011; 2011:383087. [PMID: 22203900 PMCID: PMC3238412 DOI: 10.1155/2011/383087] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 09/05/2011] [Accepted: 09/05/2011] [Indexed: 12/25/2022] Open
Abstract
Multiple sclerosis (MS) is a progressive inflammatory and demyelinating disease that affects more than 2.5 million people worldwide every year. Current therapies use mostly disease-modifying drugs, focusing on blocking and regulating systemic functions and the central nervous system (CNS) infiltration of immune cells; however, these therapies only attenuate or delay MS symptoms, but are not effective in halting the disease progression. More recent evidence indicated that regulation of inflammation within the CNS might be a better way to approach the treatment of the disease and microglia, the resident immune cells, may be a promising target of therapeutic studies. Microglia activation classically accompanies MS development, and regulation of microglia function changes the outcome of the disease. In this paper, we review the contributions of microglia to MS pathogenesis and discuss microglial functions in antigen presentation, cytokine release, and phagocytosis. We describe data both from animal and human studies. The significant impact of the timing, intensity, and differentiation fate of activated microglia is discussed, as they can modulate MS outcomes and potentially be critically modified for future therapeutic studies.
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50
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Hejčl A, Jendelová P, Syková E. Experimental reconstruction of the injured spinal cord. Adv Tech Stand Neurosurg 2011:65-95. [PMID: 21997741 DOI: 10.1007/978-3-7091-0673-0_3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Injury to the spinal cord, with its pathological sequelae, results in a permanent neurological deficit. With currently available tools at hand, there is very little that clinicians can do to treat such a condition with the view of helping patients with spinal cord injury (SCI). On the other hand, in the last 20 years experimental research has brought new insights into the pathophysiology of spinal cord injury; we can divide the time course into 3 phases: primary injury (the time of traumatic impact and the period immediately afterwards), the secondary phase (cell death, inflammation, ischemia), and the chronic phase (scarring, demyelination, cyst formation). Increased knowledge about the pathophysiology of SCI can stimulate the development of new therapeutic modalities and approaches, which may be feasible in the future in clinical practice. Some of the most promising experimental therapies include: neurotrophic factors, enzymes and antibodies against inhibitory molecules (such as Nogo), activated macrophages, stem cells and bridging scaffolds. Their common goal is to reconstitute the damaged tissue in order to recover the lost function. In the current review, we focus on some of the recent developments in experimental SCI research.
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Affiliation(s)
- A Hejčl
- Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
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