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Garton T, Gadani SP, Gill AJ, Calabresi PA. Neurodegeneration and demyelination in multiple sclerosis. Neuron 2024; 112:3231-3251. [PMID: 38889714 PMCID: PMC11466705 DOI: 10.1016/j.neuron.2024.05.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 06/20/2024]
Abstract
Progressive multiple sclerosis (PMS) is an immune-initiated neurodegenerative condition that lacks effective therapies. Although peripheral immune infiltration is a hallmark of relapsing-remitting MS (RRMS), PMS is associated with chronic, tissue-restricted inflammation and disease-associated reactive glial states. The effector functions of disease-associated microglia, astrocytes, and oligodendrocyte lineage cells are beginning to be defined, and recent studies have made significant progress in uncovering their pathologic implications. In this review, we discuss the immune-glia interactions that underlie demyelination, failed remyelination, and neurodegeneration with a focus on PMS. We highlight the common and divergent immune mechanisms by which glial cells acquire disease-associated phenotypes. Finally, we discuss recent advances that have revealed promising novel therapeutic targets for the treatment of PMS and other neurodegenerative diseases.
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Affiliation(s)
- Thomas Garton
- Division of Neuroimmunology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sachin P Gadani
- Division of Neuroimmunology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alexander J Gill
- Division of Neuroimmunology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Peter A Calabresi
- Division of Neuroimmunology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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2
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Bernis ME, Hakvoort C, Nacarkucuk E, Burkard H, Bremer AS, Zweyer M, Maes E, Grzelak KA, Sabir H. Neuroprotective Effect of Clemastine Improved Oligodendrocyte Proliferation through the MAPK/ERK Pathway in a Neonatal Hypoxia Ischemia Rat Model. Int J Mol Sci 2024; 25:8204. [PMID: 39125778 PMCID: PMC11311837 DOI: 10.3390/ijms25158204] [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: 05/08/2024] [Revised: 07/16/2024] [Accepted: 07/20/2024] [Indexed: 08/12/2024] Open
Abstract
Neonatal hypoxic-ischemic encephalopathy is the most common cause of long-term disability in term neonates, and white matter injury is the primary cause of cerebral palsy. Therapies that focus on the neuroprotection of myelination and oligodendrocyte proliferation could potentially ameliorate long-lasting neurological impairments after hypoxic-ischemic encephalopathy. Clemastine, a histamine H1 antagonist, has been shown to exert neuroprotective effects in multiple sclerosis and spinal cord injury by promoting oligodendrogenesis and re-myelination. In this study, we demonstrated the neuroprotective effects of clemastine in our rat model of neonatal hypoxic-ischemic brain injury. Animals received a single intraperitoneal injection of either vehicle or clemastine (10 mg/kg) for 6 consecutive days. Our results showed a significant reduction in white matter loss after treatment, with a clear effect of clemastine on oligodendrocytes, showing a significant increase in the number of Olig2+ cells. We characterized the MAPK/ERK pathway as a potential mechanistic pathway underlying the neuroprotective effects of clemastine. Altogether, our results demonstrate that clemastine is a potential compound for the treatment of hypoxic-ischemic encephalopathy, with a clear neuroprotective effect on white matter injury by promoting oligodendrogenesis.
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Affiliation(s)
- Maria E. Bernis
- Neonatologie und Pädiatrische Intensivmedizin, Eltern-Kind-Zentrum, Universitätsklinikum Bonn, 53127 Bonn, Germany; (M.E.B.); (C.H.); (E.N.); (H.B.); (A.-S.B.); (M.Z.); (E.M.); (K.A.G.)
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
| | - Charlotte Hakvoort
- Neonatologie und Pädiatrische Intensivmedizin, Eltern-Kind-Zentrum, Universitätsklinikum Bonn, 53127 Bonn, Germany; (M.E.B.); (C.H.); (E.N.); (H.B.); (A.-S.B.); (M.Z.); (E.M.); (K.A.G.)
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
| | - Efe Nacarkucuk
- Neonatologie und Pädiatrische Intensivmedizin, Eltern-Kind-Zentrum, Universitätsklinikum Bonn, 53127 Bonn, Germany; (M.E.B.); (C.H.); (E.N.); (H.B.); (A.-S.B.); (M.Z.); (E.M.); (K.A.G.)
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
| | - Hannah Burkard
- Neonatologie und Pädiatrische Intensivmedizin, Eltern-Kind-Zentrum, Universitätsklinikum Bonn, 53127 Bonn, Germany; (M.E.B.); (C.H.); (E.N.); (H.B.); (A.-S.B.); (M.Z.); (E.M.); (K.A.G.)
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
| | - Anna-Sophie Bremer
- Neonatologie und Pädiatrische Intensivmedizin, Eltern-Kind-Zentrum, Universitätsklinikum Bonn, 53127 Bonn, Germany; (M.E.B.); (C.H.); (E.N.); (H.B.); (A.-S.B.); (M.Z.); (E.M.); (K.A.G.)
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
| | - Margit Zweyer
- Neonatologie und Pädiatrische Intensivmedizin, Eltern-Kind-Zentrum, Universitätsklinikum Bonn, 53127 Bonn, Germany; (M.E.B.); (C.H.); (E.N.); (H.B.); (A.-S.B.); (M.Z.); (E.M.); (K.A.G.)
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
| | - Elke Maes
- Neonatologie und Pädiatrische Intensivmedizin, Eltern-Kind-Zentrum, Universitätsklinikum Bonn, 53127 Bonn, Germany; (M.E.B.); (C.H.); (E.N.); (H.B.); (A.-S.B.); (M.Z.); (E.M.); (K.A.G.)
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
| | - Kora A. Grzelak
- Neonatologie und Pädiatrische Intensivmedizin, Eltern-Kind-Zentrum, Universitätsklinikum Bonn, 53127 Bonn, Germany; (M.E.B.); (C.H.); (E.N.); (H.B.); (A.-S.B.); (M.Z.); (E.M.); (K.A.G.)
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
| | - Hemmen Sabir
- Neonatologie und Pädiatrische Intensivmedizin, Eltern-Kind-Zentrum, Universitätsklinikum Bonn, 53127 Bonn, Germany; (M.E.B.); (C.H.); (E.N.); (H.B.); (A.-S.B.); (M.Z.); (E.M.); (K.A.G.)
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
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3
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Zveik O, Rechtman A, Ganz T, Vaknin-Dembinsky A. The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells. Mol Neurodegener 2024; 19:53. [PMID: 38997755 PMCID: PMC11245841 DOI: 10.1186/s13024-024-00742-8] [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: 05/29/2024] [Accepted: 07/01/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND Multiple sclerosis (MS) therapeutic goals have traditionally been dichotomized into two distinct avenues: immune-modulatory-centric interventions and pro-regenerative strategies. Oligodendrocyte progenitor cells (OPCs) were regarded for many years solely in concern to their potential to generate oligodendrocytes and myelin in the central nervous system (CNS). However, accumulating data elucidate the multifaceted roles of OPCs, including their immunomodulatory functions, positioning them as cardinal constituents of the CNS's immune landscape. MAIN BODY In this review, we will discuss how the two therapeutic approaches converge. We present a model by which (1) an inflammation is required for the appropriate pro-myelinating immune function of OPCs in the chronically inflamed CNS, and (2) the immune function of OPCs is crucial for their ability to differentiate and promote remyelination. This model highlights the reciprocal interactions between OPCs' pro-myelinating and immune-modulating functions. Additionally, we review the specific effects of anti- and pro-inflammatory interventions on OPCs, suggesting that immunosuppression adversely affects OPCs' differentiation and immune functions. CONCLUSION We suggest a multi-systemic therapeutic approach, which necessitates not a unidimensional focus but a harmonious balance between OPCs' pro-myelinating and immune-modulatory functions.
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Affiliation(s)
- Omri Zveik
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Kerem P.O.B. 12000, Jerusalem, 91120, Israel
| | - Ariel Rechtman
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Kerem P.O.B. 12000, Jerusalem, 91120, Israel
| | - Tal Ganz
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Kerem P.O.B. 12000, Jerusalem, 91120, Israel
| | - Adi Vaknin-Dembinsky
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel.
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Kerem P.O.B. 12000, Jerusalem, 91120, Israel.
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Franklin RJM, Bodini B, Goldman SA. Remyelination in the Central Nervous System. Cold Spring Harb Perspect Biol 2024; 16:a041371. [PMID: 38316552 PMCID: PMC10910446 DOI: 10.1101/cshperspect.a041371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
The inability of the mammalian central nervous system (CNS) to undergo spontaneous regeneration has long been regarded as a central tenet of neurobiology. However, while this is largely true of the neuronal elements of the adult mammalian CNS, save for discrete populations of granule neurons, the same is not true of its glial elements. In particular, the loss of oligodendrocytes, which results in demyelination, triggers a spontaneous and often highly efficient regenerative response, remyelination, in which new oligodendrocytes are generated and myelin sheaths are restored to denuded axons. Yet remyelination in humans is not without limitation, and a variety of demyelinating conditions are associated with sustained and disabling myelin loss. In this work, we will (1) review the biology of remyelination, including the cells and signals involved; (2) describe when remyelination occurs and when and why it fails, including the consequences of its failure; and (3) discuss approaches for therapeutically enhancing remyelination in demyelinating diseases of both children and adults, both by stimulating endogenous oligodendrocyte progenitor cells and by transplanting these cells into demyelinated brain.
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Affiliation(s)
- Robin J M Franklin
- Altos Labs Cambridge Institute of Science, Cambridge CB21 6GH, United Kingdom
| | - Benedetta Bodini
- Sorbonne Université, Paris Brain Institute, CNRS, INSERM, Paris 75013, France
- Saint-Antoine Hospital, APHP, Paris 75012, France
| | - Steven A Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA
- University of Copenhagen Faculty of Medicine, Copenhagen 2200, Denmark
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5
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Kim M, Kim WS, Cha H, Kim B, Kwon YN, Kim SM. Early involvement of peripherally derived monocytes in inflammation in an NMO-like mouse model. Sci Rep 2024; 14:1177. [PMID: 38216632 PMCID: PMC10786844 DOI: 10.1038/s41598-024-51759-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 01/09/2024] [Indexed: 01/14/2024] Open
Abstract
Neuromyelitis optica (NMO) is an autoimmune inflammatory disease that primarily affects the optic nerve and spinal cord within the central nervous system (CNS). Acute astrocyte injury caused by autoantibodies against aquaporin 4 (NMO-IgG) is a well-established key factor in the pathogenesis, ultimately leading to neuronal damage and patient disability. In addition to these humoral immune processes, numerous innate immune cells were found in the acute lesions of NMO patients. However, the origin and function of these innate immune cells remain unclear in NMO pathogenesis. Therefore, this study aims to analyze the origin and functions of these innate immune cells in an NMO-like mouse model and evaluate their role in the pathophysiology of NMO. The expression of Tmem119 on Iba1 + cells in brain tissue disappeared immediately after the injection of NMO-IgG + human complement mixture, while the expression of P2ry12 remained well-maintained at 1 day after injection. Based on these observations, it was demonstrated that monocytes infiltrate the brain during the early stages of the pathological process and are closely associated with the inflammatory response through the expression of the proinflammatory cytokine IL-1β. Understanding the variations in the expression patterns of P2ry12, Tmem119, and other markers could be helpful in distinguishing between these cell types and further analyzing their functions. Therefore, this research may contribute to a better understanding of the mechanisms and potential treatments for NMO.
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Affiliation(s)
- Moonhang Kim
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03082, Republic of Korea.
| | - Won Seok Kim
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03082, Republic of Korea
| | - Hyeuk Cha
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03082, Republic of Korea
| | - Boram Kim
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03082, Republic of Korea
| | - Young Nam Kwon
- Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Sung Min Kim
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
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6
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Harry GJ. Microglia Colonization Associated with Angiogenesis and Neural Cell Development. ADVANCES IN NEUROBIOLOGY 2024; 37:163-178. [PMID: 39207692 DOI: 10.1007/978-3-031-55529-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
The temporal and spatial pattern of microglia colonization of the nervous system implies a role in early stages of organ development including cell proliferation, differentiation, and neurovascularization. As microglia colonize and establish within the developing nervous system, they assume a neural-specific identity and contribute to key developmental events. Their association around blood vessels implicates them in development of the vascular system or vice versa. A similar association has been reported for neural cell proliferation and associated phenotypic shifts and for cell fate differentiation to neuronal or glial phenotypes. These processes are accomplished by phagocytic activities, cell-cell contact relationships, and secretion of various factors. This chapter will present data currently available from studies evaluating the dynamic and interactive nature of these processes throughout the progression of nervous system development.
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Affiliation(s)
- G Jean Harry
- Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute Environmental Health Sciences, Research Triangle Park, NC, USA.
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7
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Baaklini CS, Ho MFS, Lange T, Hammond BP, Panda SP, Zirngibl M, Zia S, Himmelsbach K, Rana H, Phillips B, Antoszko D, Ibanga J, Lopez M, Lee KV, Keough MB, Caprariello AV, Kerr BJ, Plemel JR. Microglia promote remyelination independent of their role in clearing myelin debris. Cell Rep 2023; 42:113574. [PMID: 38100356 DOI: 10.1016/j.celrep.2023.113574] [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: 05/18/2023] [Revised: 10/17/2023] [Accepted: 11/27/2023] [Indexed: 12/17/2023] Open
Abstract
Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss. While therapies exist to slow MS progression, no treatment currently exists for remyelination. Remyelination, linked to reduced disability in MS, relies on microglia and monocyte-derived macrophages (MDMs). This study aims to understand the role of microglia during remyelination by lineage tracing and depleting them. Microglial lineage tracing reveals that both microglia and MDMs initially accumulate, but microglia later dominate the lesion. Microglia and MDMs engulf equal amounts of inhibitory myelin debris, but after microglial depletion, MDMs compensate by engulfing more myelin debris. Microglial depletion does, however, reduce the recruitment and proliferation of oligodendrocyte progenitor cells (OPCs) and impairs their subsequent differentiation and remyelination. These findings underscore the essential role of microglia during remyelination and offer insights for enhancing this process by understanding microglial regulation of remyelination.
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Affiliation(s)
- Charbel S Baaklini
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Madelene F S Ho
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Tristan Lange
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Brady P Hammond
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Sharmistha P Panda
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Martin Zirngibl
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Sameera Zia
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Kassandre Himmelsbach
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Heli Rana
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Braxton Phillips
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Daria Antoszko
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Jeremies Ibanga
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Mizuki Lopez
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Kelly V Lee
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Michael B Keough
- Division of Neurosurgery, Department of Surgery, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Andrew V Caprariello
- Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Cumming School of Medicine, Calgary, AB T2N 1N4, Canada
| | - Bradley J Kerr
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada; Department of Anesthesiology & Pain Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Jason R Plemel
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2R3, Canada; Department of Medicine, Division of Neurology, University of Alberta, Edmonton, AB T6G 2R3, Canada.
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Fabres RB, Cardoso DS, Aragón BA, Arruda BP, Martins PP, Ikebara JM, Drobyshevsky A, Kihara AH, de Fraga LS, Netto CA, Takada SH. Consequences of oxygen deprivation on myelination and sex-dependent alterations. Mol Cell Neurosci 2023; 126:103864. [PMID: 37268283 DOI: 10.1016/j.mcn.2023.103864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/07/2023] [Accepted: 05/25/2023] [Indexed: 06/04/2023] Open
Abstract
Oxygen deprivation is one of the main causes of morbidity and mortality in newborns, occurring with a higher prevalence in preterm infants, reaching 20 % to 50 % mortality in newborns in the perinatal period. When they survive, 25 % exhibit neuropsychological pathologies, such as learning difficulties, epilepsy, and cerebral palsy. White matter injury is one of the main features found in oxygen deprivation injury, which can lead to long-term functional impairments, including cognitive delay and motor deficits. The myelin sheath accounts for much of the white matter in the brain by surrounding axons and enabling the efficient conduction of action potentials. Mature oligodendrocytes, which synthesize and maintain myelination, also comprise a significant proportion of the brain's white matter. In recent years, oligodendrocytes and the myelination process have become potential therapeutic targets to minimize the effects of oxygen deprivation on the central nervous system. Moreover, evidence indicate that neuroinflammation and apoptotic pathways activated during oxygen deprivation may be influenced by sexual dimorphism. To summarize the most recent research about the impact of sexual dimorphism on the neuroinflammatory state and white matter injury after oxygen deprivation, this review presents an overview of the oligodendrocyte lineage development and myelination, the impact of oxygen deprivation and neuroinflammation on oligodendrocytes in neurodevelopmental disorders, and recent reports about sexual dimorphism regarding the neuroinflammation and white matter injury after neonatal oxygen deprivation.
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Affiliation(s)
- Rafael Bandeira Fabres
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos, 2600, Porto Alegre 90035-003, Brazil
| | - Débora Sterzeck Cardoso
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil
| | | | - Bruna Petrucelli Arruda
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil
| | - Pamela Pinheiro Martins
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil
| | - Juliane Midori Ikebara
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil
| | | | - Alexandre Hiroaki Kihara
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil
| | - Luciano Stürmer de Fraga
- Departamento de Fisiologia, Universidade Federal do Rio Grande do Sul (UFRGS), Sarmento Leite, 500, Porto Alegre 90050-170, Brazil
| | - Carlos Alexandre Netto
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos, 2600, Porto Alegre 90035-003, Brazil
| | - Silvia Honda Takada
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil.
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9
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Wang L, Lu X, Chopp M, Li C, Zhang Y, Szalad A, Liu XS, Zhang ZG. Comparative proteomic analysis of exosomes derived from endothelial cells and Schwann cells. PLoS One 2023; 18:e0290155. [PMID: 37594969 PMCID: PMC10437921 DOI: 10.1371/journal.pone.0290155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/02/2023] [Indexed: 08/20/2023] Open
Abstract
Exosomes derived from endothelial cells and Schwann cells have been employed as novel treatments of neurological diseases, including peripheral neuropathy. Exosomal cargo plays a critical role in mediating recipient cell function. In this study, we thus performed a comprehensive proteomic analysis of exosomes derived from healthy mouse dermal microvascular endothelial cells (EC-Exo) and healthy mouse Schwann cells (SC-Exo). We detected 1,817and 1,579 proteins in EC-Exo and SC-Exo, respectively. Among them, 1506 proteins were present in both EC-Exo and SC-Exo, while 311 and 73 proteins were detected only in EC-Exo and SC-Exo, respectively. Bioinformatic analysis revealed that EC-Exo enriched proteins were involved in neurovascular function, while SC-Exo enriched proteins were related to lipid metabolism. Western blot analysis of 14 enriched proteins revealed that EC-Exo contained proteins involved in mediating endothelial function such as delta-like 4 (DLL4) and endothelial NOS (NOS3), whereas SC-Exo had proteins involved in mediating glial function such as apolipoprotein A-I (APOA1) and phospholipid transfer protein (PLTP). Collectively, the present study identifies differences in the cargo protein profiles of EC-Exo and SC-Exo, thus providing new molecular insights into their biological functions for the treatment of peripheral neuropathy.
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Affiliation(s)
- Lei Wang
- Department of Neurology, Henry Ford Health, Detroit, Michigan, United States of America
| | - XueRong Lu
- Department of Neurology, Henry Ford Health, Detroit, Michigan, United States of America
| | - Michael Chopp
- Department of Neurology, Henry Ford Health, Detroit, Michigan, United States of America
- Department of Physics, Oakland University, Rochester, Michigan, United States of America
| | - Chao Li
- Department of Neurology, Henry Ford Health, Detroit, Michigan, United States of America
| | - Yi Zhang
- Department of Neurology, Henry Ford Health, Detroit, Michigan, United States of America
| | - Alexandra Szalad
- Department of Neurology, Henry Ford Health, Detroit, Michigan, United States of America
| | - Xian Shuang Liu
- Department of Neurology, Henry Ford Health, Detroit, Michigan, United States of America
| | - Zheng Gang Zhang
- Department of Neurology, Henry Ford Health, Detroit, Michigan, United States of America
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10
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Sager REH, Walker AK, Middleton FA, Robinson K, Webster MJ, Gentile K, Wong ML, Shannon Weickert C. Changes in cytokine and cytokine receptor levels during postnatal development of the human dorsolateral prefrontal cortex. Brain Behav Immun 2023; 111:186-201. [PMID: 36958512 DOI: 10.1016/j.bbi.2023.03.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 03/09/2023] [Accepted: 03/16/2023] [Indexed: 03/25/2023] Open
Abstract
In addition to their traditional roles in immune cell communication, cytokines regulate brain development. Cytokines are known to influence neural cell generation, differentiation, maturation, and survival. However, most work on the role of cytokines in brain development investigates rodents or focuses on prenatal events. Here, we investigate how mRNA and protein levels of key cytokines and cytokine receptors change during postnatal development of the human prefrontal cortex. We find that most cytokine transcripts investigated (IL1B, IL18, IL6, TNF, IL13) are lowest at birth and increase between 1.5 and 5 years old. After 5 years old, transcriptional patterns proceeded in one of two directions: decreased expression in teens and young adults (IL1B, p = 0.002; and IL18, p = 0.004) or increased mean expression with maturation, particularly in teenagers (IL6, p = 0.004; TNF, p = 0.002; IL13, p < 0.001). In contrast, cytokine proteins tended to remain elevated after peaking significantly around 3 years of age (IL1B, p = 0.012; IL18, p = 0.026; IL6, p = 0.039; TNF, p < 0.001), with TNF protein being highest in teenagers. An mRNA-only analysis of cytokine receptor transcripts found that early developmental increases in cytokines were paralleled by increases in their ligand-binding receptor subunits, such as IL1R1 (p = 0.033) and IL6R (p < 0.001) transcripts. In contrast, cytokine receptor-associated signaling subunits, IL1RAP and IL6ST, did not change significantly between age groups. Of the two TNF receptors, the 'pro-death' TNFRSF1A and 'pro-survival' TNFRSF1B, only TNFRSF1B was significantly changed (p = 0.028), increasing first in toddlers and again in young adults. Finally, the cytokine inhibitor, IL13, was elevated first in toddlers (p = 0.006) and again in young adults (p = 0.053). While the mean expression of interleukin-1 receptor antagonist (IL1RN) was highest in toddlers, this increase was not statistically significant. The fluctuations in cytokine expression reported here support a role for increases in specific cytokines at two different stages of human cortical development. The first is during the toddler/preschool period (IL1B, IL18, and IL13), and the other occurs at adolescence/young adult maturation (IL6, TNF and IL13).
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Affiliation(s)
- Rachel E H Sager
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Adam K Walker
- Laboratory of Immunopsychiatry, Neuroscience Research Australia, Sydney, NSW, Australia; Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, NSW, Australia; Monash Institute of Pharmaceutical Science, Monash University, Parkville, VIC, Australia
| | - Frank A Middleton
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Kate Robinson
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, NSW, Australia
| | | | - Karen Gentile
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Ma-Li Wong
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA; Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Cynthia Shannon Weickert
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA; Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, NSW, Australia; Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, NSW, Australia.
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11
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Distéfano-Gagné F, Bitarafan S, Lacroix S, Gosselin D. Roles and regulation of microglia activity in multiple sclerosis: insights from animal models. Nat Rev Neurosci 2023:10.1038/s41583-023-00709-6. [PMID: 37268822 DOI: 10.1038/s41583-023-00709-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2023] [Indexed: 06/04/2023]
Abstract
As resident macrophages of the CNS, microglia are critical immune effectors of inflammatory lesions and associated neural dysfunctions. In multiple sclerosis (MS) and its animal models, chronic microglial inflammatory activity damages myelin and disrupts axonal and synaptic activity. In contrast to these detrimental effects, the potent phagocytic and tissue-remodelling capabilities of microglia support critical endogenous repair mechanisms. Although these opposing capabilities have long been appreciated, a precise understanding of their underlying molecular effectors is only beginning to emerge. Here, we review recent advances in our understanding of the roles of microglia in animal models of MS and demyelinating lesions and the mechanisms that underlie their damaging and repairing activities. We also discuss how the structured organization and regulation of the genome enables complex transcriptional heterogeneity within the microglial cell population at demyelinating lesions.
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Affiliation(s)
- Félix Distéfano-Gagné
- Axe Neuroscience, Centre de Recherche du CHU de Québec - Université Laval, Québec, Québec, Canada
- Département de Médecine Moléculaire de la Faculté de Médecine, Université Laval, Québec, Québec, Canada
| | - Sara Bitarafan
- Axe Neuroscience, Centre de Recherche du CHU de Québec - Université Laval, Québec, Québec, Canada
- Département de Médecine Moléculaire de la Faculté de Médecine, Université Laval, Québec, Québec, Canada
| | - Steve Lacroix
- Axe Neuroscience, Centre de Recherche du CHU de Québec - Université Laval, Québec, Québec, Canada
- Département de Médecine Moléculaire de la Faculté de Médecine, Université Laval, Québec, Québec, Canada
| | - David Gosselin
- Axe Neuroscience, Centre de Recherche du CHU de Québec - Université Laval, Québec, Québec, Canada.
- Département de Médecine Moléculaire de la Faculté de Médecine, Université Laval, Québec, Québec, Canada.
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12
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Dong G, Kogan S, Venugopal N, Chang E, He L, Faal F, Shi Y, Phillips McCluskey L. Interleukin (IL)-1 Receptor Signaling Is Required for Complete Taste Bud Regeneration and the Recovery of Neural Taste Responses following Axotomy. J Neurosci 2023; 43:3439-3455. [PMID: 37015809 PMCID: PMC10184746 DOI: 10.1523/jneurosci.1355-22.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 03/03/2023] [Accepted: 03/07/2023] [Indexed: 04/06/2023] Open
Abstract
Experimental or traumatic nerve injury causes the degeneration of associated taste buds. Unlike most sensory systems, the sectioned nerve and associated taste buds can then regenerate, restoring neural responses to tastants. It was previously unknown whether injury-induced immune factors mediate this process. The proinflammatory cytokines, interleukin (IL)-1α and IL-1β, and their requisite receptor are strongly expressed by anterior taste buds innervated by the chorda tympani nerve. We tested taste bud regeneration and functional recovery in mice lacking the IL-1 receptor. After axotomy, the chorda tympani nerve regenerated but was initially unresponsive to tastants in both WT and Il1r KO mice. In the absence of Il1r signaling, however, neural taste responses remained minimal even >8 weeks after injury in both male and female mice, whereas normal taste function recovered by 3 weeks in WT mice. Failed recovery was because of a 57.8% decrease in regenerated taste buds in Il1r KO compared with WT axotomized mice. Il1a gene expression was chronically dysregulated, and the subset of regenerated taste buds were reinnervated more slowly and never reached full volume as progenitor cell proliferation lagged in KO mice. Il1r signaling is thus required for complete taste bud regeneration and the recovery of normal taste transmission, likely by impairing taste progenitor cell proliferation. This is the first identification of a cytokine response that promotes taste recovery. The remarkable plasticity of the taste system makes it ideal for identifying injury-induced mechanisms mediating successful regeneration and recovery.SIGNIFICANCE STATEMENT Taste plays a critical role in nutrition and quality of life. The adult taste system is highly plastic and able to regenerate following the disappearance of most taste buds after experimental nerve injury. Several growth factors needed for taste bud regeneration have been identified, but we demonstrate the first cytokine pathway required for the recovery of taste function. In the absence of IL-1 cytokine signaling, taste bud regeneration is incomplete, preventing the transmission of taste activity to the brain. These results open a new direction in revealing injury-specific mechanisms that could be harnessed to promote the recovery of taste perception after trauma or disease.
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Affiliation(s)
- Guangkuo Dong
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912
| | - Schuyler Kogan
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912
| | - Natasha Venugopal
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912
| | - Eddy Chang
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912
| | - Lianying He
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912
| | - Fama Faal
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912
| | - Yang Shi
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912
- Division of Biostatistics and Data Science, Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, Georgia 30912
| | - Lynnette Phillips McCluskey
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912
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13
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Wang Y, Kyauk RV, Shen YAA, Xie L, Reichelt M, Lin H, Jiang Z, Ngu H, Shen K, Greene JJ, Sheng M, Yuen TJ. TREM2-dependent microglial function is essential for remyelination and subsequent neuroprotection. Glia 2023; 71:1247-1258. [PMID: 36625077 DOI: 10.1002/glia.24335] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 12/23/2022] [Accepted: 12/27/2022] [Indexed: 01/11/2023]
Abstract
Disability in multiple sclerosis (MS) is driven in part by the failure of remyelination and progressive neurodegeneration. Microglia, and specifically triggering receptor expressed on myeloid cells 2 (TREM2), a factor highly expressed in microglia, have been shown to play an important role in remyelination. Here, using a focal demyelination model in the brain, we demonstrate that demyelination is persistent in TREM2 knockout mice, lasting more than 6 weeks after lysolecithin injection and resulting in substantial neurodegeneration. We also find that TREM2 knockout mice exhibit an altered glial response following demyelination. TREM2 knockout microglia demonstrate defects in migration and phagocytosis of myelin debris. In addition, human monocyte-derived macrophages from subjects with a TREM2 mutation prevalent in human disease also show a defect in myelin debris phagocytosis. Together, we highlight the central role of TREM2 signaling in remyelination and neuroprotection. These findings provide insights into how chronic demyelination might lead to axonal damage and could help identify novel neuroprotective therapeutic targets for MS.
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Affiliation(s)
- Yuanyuan Wang
- Department of Neuroscience, Genentech Inc., South San Francisco, California, USA
| | - Roxanne V Kyauk
- Department of Neuroscience, Genentech Inc., South San Francisco, California, USA
| | - Yun-An A Shen
- Department of Neuroscience, Genentech Inc., South San Francisco, California, USA
| | - Luke Xie
- Department of Biomedical Imaging, Genentech Inc., South San Francisco, California, USA
| | - Mike Reichelt
- Department of Pathology, Genentech Inc., South San Francisco, California, USA
| | - Han Lin
- Department of Neuroscience, Genentech Inc., South San Francisco, California, USA
| | - Zhiyu Jiang
- Department of Neuroscience, Genentech Inc., South San Francisco, California, USA
| | - Hai Ngu
- Department of Pathology, Genentech Inc., South San Francisco, California, USA
| | - Kimberle Shen
- Department of Neuroscience, Genentech Inc., South San Francisco, California, USA
| | - Jacob J Greene
- Department of Neuroscience, Genentech Inc., South San Francisco, California, USA
| | - Morgan Sheng
- Department of Neuroscience, Genentech Inc., South San Francisco, California, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Tracy J Yuen
- Department of Neuroscience, Genentech Inc., South San Francisco, California, USA
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14
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Kremsky I, Ma Q, Li B, Dasgupta C, Chen X, Ali S, Angeloni S, Wang C, Zhang L. Fetal hypoxia results in sex- and cell type-specific alterations in neonatal transcription in rat oligodendrocyte precursor cells, microglia, neurons, and oligodendrocytes. Cell Biosci 2023; 13:58. [PMID: 36932456 PMCID: PMC10022003 DOI: 10.1186/s13578-023-01012-8] [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: 11/23/2022] [Accepted: 03/10/2023] [Indexed: 03/19/2023] Open
Abstract
BACKGROUND Fetal hypoxia causes vital, systemic, developmental malformations in the fetus, particularly in the brain, and increases the risk of diseases in later life. We previously demonstrated that fetal hypoxia exposure increases the susceptibility of the neonatal brain to hypoxic-ischemic insult. Herein, we investigate the effect of fetal hypoxia on programming of cell-specific transcriptomes in the brain of neonatal rats. RESULTS We obtained RNA sequencing (RNA-seq) data from neurons, microglia, oligodendrocytes, A2B5+ oligodendrocyte precursor cells, and astrocytes from male and female neonatal rats subjected either to fetal hypoxia or control conditions. Substantial transcriptomic responses to fetal hypoxia occurred in neurons, microglia, oligodendrocytes, and A2B5+ cells. Not only were the transcriptomic responses unique to each cell type, but they also occurred with a great deal of sexual dimorphism. We validated differential expression of several genes related to inflammation and cell death by Real-time Quantitative Polymerase Chain Reaction (qRT-PCR). Pathway and transcription factor motif analyses suggested that the NF-kappa B (NFκB) signaling pathway was enriched in the neonatal male brain due to fetal hypoxia, and we verified this result by transcription factor assay of NFκB-p65 in whole brain. CONCLUSIONS Our study reveals a significant impact of fetal hypoxia on the transcriptomes of neonatal brains in a cell-specific and sex-dependent manner, and provides mechanistic insights that may help explain the development of hypoxic-ischemic sensitive phenotypes in the neonatal brain.
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Affiliation(s)
- Isaac Kremsky
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.,Center for Genomics, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Qingyi Ma
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.,Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA
| | - Bo Li
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA
| | - Chiranjib Dasgupta
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA
| | - Xin Chen
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.,Center for Genomics, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Samir Ali
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Shawnee Angeloni
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Charles Wang
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.,Center for Genomics, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Lubo Zhang
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA. .,Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.
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15
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Vanherle S, Jorissen W, Dierckx T, Loix M, Grajchen E, Mingneau F, Guns J, Gervois P, Lambrichts I, Dehairs J, Swinnen JV, Mulder MT, Remaley AT, Haidar M, Hendriks JJ, Bogie JJ. The ApoA-I mimetic peptide 5A enhances remyelination by promoting clearance and degradation of myelin debris. Cell Rep 2022; 41:111591. [DOI: 10.1016/j.celrep.2022.111591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 09/09/2022] [Accepted: 10/11/2022] [Indexed: 11/09/2022] Open
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16
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Haidar M, Loix M, Vanherle S, Dierckx T, Vangansewinkel T, Gervois P, Wolfs E, Lambrichts I, Bogie JFJ, Hendriks JJA. Targeting lipophagy in macrophages improves repair in multiple sclerosis. Autophagy 2022; 18:2697-2710. [PMID: 35282773 PMCID: PMC9629102 DOI: 10.1080/15548627.2022.2047343] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Foamy macrophages containing abundant intracellular myelin remnants are an important pathological hallmark of multiple sclerosis. Reducing the intracellular lipid burden in foamy macrophages is considered a promising therapeutic strategy to induce a phagocyte phenotype that promotes central nervous system repair. Recent research from our group showed that sustained intracellular accumulation of myelin-derived lipids skews these phagocytes toward a disease-promoting and more inflammatory phenotype. Our data now demonstrate that disturbed lipophagy, a selective form of autophagy that helps with the degradation of lipid droplets, contributes to the induction of this phenotype. Stimulating autophagy using the natural disaccharide trehalose reduced the lipid load and inflammatory phenotype of myelin-laden macrophages. Importantly, trehalose was able to boost remyelination in the ex vivo brain slice model and the in vivo cuprizone-induced demyelination model. In summary, our results provide a molecular rationale for impaired metabolism of myelin-derived lipids in macrophages, and identify lipophagy induction as a promising treatment strategy to promote remyelination.Abbreviations: Baf: bafilomycin a1; BMDM: bone marrow-derived macrophage; CD68: CD68 antigen; CNS: central nervous system; LD: lipid droplet; LIPE/HSL: lipase, hormone sensitive; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MBP: myelin basic protein; MGLL: monoglyceride lipase; MS: multiple sclerosis; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2, inducible; ORO: oil red o; PNPLA2: patatin-like phospholipase domain containing 2; PLIN2: perilipin 2; TEM: transmission electron microscopy; TFEB: transcription factor EB; TOH: trehalose.
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Affiliation(s)
- Mansour Haidar
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Melanie Loix
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Sam Vanherle
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Tess Dierckx
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Tim Vangansewinkel
- Department of Cardio and Organs Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Pascal Gervois
- Department of Cardio and Organs Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Esther Wolfs
- Department of Cardio and Organs Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Ivo Lambrichts
- Department of Cardio and Organs Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Jeroen F J Bogie
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Jerome J A Hendriks
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
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17
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The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury. Nat Commun 2022; 13:5786. [PMID: 36184639 PMCID: PMC9527244 DOI: 10.1038/s41467-022-33463-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 09/16/2022] [Indexed: 01/18/2023] Open
Abstract
Spinal cord injury (SCI) triggers neuroinflammation, and subsequently secondary degeneration and oligodendrocyte (OL) death. We report that the alarmin interleukin (IL)-1α is produced by damaged microglia after SCI. Intra-cisterna magna injection of IL-1α in mice rapidly induces neutrophil infiltration and OL death throughout the spinal cord, mimicking the injury cascade seen in SCI sites. These effects are abolished through co-treatment with the IL-1R1 antagonist anakinra, as well as in IL-1R1-knockout mice which demonstrate enhanced locomotor recovery after SCI. Conditional restoration of IL-1R1 expression in astrocytes or endothelial cells (ECs), but not in OLs or microglia, restores IL-1α-induced effects, while astrocyte- or EC-specific Il1r1 deletion reduces OL loss. Conditioned medium derived from IL-1α-stimulated astrocytes results in toxicity for OLs; further, IL-1α-stimulated astrocytes generate reactive oxygen species (ROS), and blocking ROS production in IL-1α-treated or SCI mice prevented OL loss. Thus, after SCI, microglia release IL-1α, inducing astrocyte- and EC-mediated OL degeneration.
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18
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Zheng H, Wang S, Li X, Hu H. INSISTC: Incorporating network structure information for single-cell type classification. Genomics 2022; 114:110480. [PMID: 36075505 DOI: 10.1016/j.ygeno.2022.110480] [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: 07/24/2022] [Revised: 08/30/2022] [Accepted: 09/04/2022] [Indexed: 11/27/2022]
Abstract
Uncovering gene regulatory mechanisms in individual cells can provide insight into cell heterogeneity and function. Recent accumulated Single-Cell RNA-Seq data have made it possible to analyze gene regulation at single-cell resolution. Understanding cell-type-specific gene regulation can assist in more accurate cell type and state identification. Computational approaches utilizing such relationships are under development. Methods pioneering in integrating gene regulatory mechanism discovery with cell-type classification encounter challenges such as determine gene regulatory relationships and incorporate gene regulatory network structure. To fill this gap, we developed INSISTC, a computational method to incorporate gene regulatory network structure information for single-cell type classification. INSISTC is capable of identifying cell-type-specific gene regulatory mechanisms while performing single-cell type classification. INSISTC demonstrated its accuracy in cell type classification and its potential for providing insight into molecular mechanisms specific to individual cells. In comparison with the alternative methods, INSISTC demonstrated its complementary performance for gene regulation interpretation.
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Affiliation(s)
- Hansi Zheng
- Department of Computer Science, University of Central Florida, Orlando, FL 32816, USA
| | - Saidi Wang
- Department of Computer Science, University of Central Florida, Orlando, FL 32816, USA
| | - Xiaoman Li
- Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
| | - Haiyan Hu
- Department of Computer Science, Genomics and Bioinformatics Cluster, University of Central Florida, Orlando, FL 32816, USA.
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19
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Kiaie N, Gorabi AM, Loveless R, Teng Y, Jamialahmadi T, Sahebkar A. The regenerative potential of glial progenitor cells and reactive astrocytes in CNS injuries. Neurosci Biobehav Rev 2022; 140:104794. [PMID: 35902044 DOI: 10.1016/j.neubiorev.2022.104794] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 10/16/2022]
Abstract
Cell therapeutic approaches focusing on the regeneration of damaged tissue have been a popular topic among researchers in recent years. In particular, self-repair scarring from the central nervous system (CNS) can significantly complicate the treatment of an injured patient. In CNS regeneration schemes, either glial progenitor cells or reactive glial cells have key roles to play. In this review, the contribution and underlying mechanisms of these progenitor/reactive glial cells during CNS regeneration are discussed, as well as their role in CNS-related diseases.
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Affiliation(s)
- Nasim Kiaie
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Armita Mahdavi Gorabi
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reid Loveless
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Yong Teng
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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20
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Yu Z, Fang X, Liu W, Sun R, Zhou J, Pu Y, Zhao M, Sun D, Xiang Z, Liu P, Ding Y, Cao L, He C. Microglia Regulate Blood-Brain Barrier Integrity via MiR-126a-5p/MMP9 Axis during Inflammatory Demyelination. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2105442. [PMID: 35758549 PMCID: PMC9403646 DOI: 10.1002/advs.202105442] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 05/14/2022] [Indexed: 05/14/2023]
Abstract
Blood-brain barrier (BBB) impairment is an early prevalent feature of multiple sclerosis (MS), and remains vital for MS progression. Microglial activation precedes BBB disruption and cellular infiltrates in the brain of MS patients. However, little is known about the function of microglia in BBB impairment. Here, microglia acts as an important modulator of BBB integrity in inflammatory demyelination. Microglial depletion profoundly ameliorates BBB impairment in experimental autoimmune encephalomyelitis (EAE). Specifically, miR-126a-5p in microglia is positively correlated with BBB integrity in four types of MS plaques. Mechanistically, microglial deletion of miR-126a-5p exacerbates BBB leakage and EAE severity. The protective effect of miR-126a-5p is mimicked and restored by specific inhibition of MMP9 in microglia. Importantly, Auranofin, an FDA-approved drug, is identified to protect BBB integrity and mitigate EAE progression via a microglial miR-126a-5p dependent mechanism. Taken together, microglia can be manipulated to protect BBB integrity and ameliorate inflammatory demyelination. Targeting microglia to regulate BBB permeability merits consideration in therapeutic interventions in MS.
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Affiliation(s)
- Zhongwang Yu
- Institute of NeuroscienceKey Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain ScienceSMMUShanghai200433China
| | - Xue Fang
- Institute of NeuroscienceKey Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain ScienceSMMUShanghai200433China
- Department of GastroenterologyChanghai HospitalSMMUShanghai200433China
| | - Weili Liu
- Institute of NeuroscienceKey Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain ScienceSMMUShanghai200433China
| | - Rui Sun
- Department of NeurologyChanghai HospitalSMMUShanghai200433China
| | - Jintao Zhou
- Institute of NeuroscienceKey Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain ScienceSMMUShanghai200433China
| | - Yingyan Pu
- Institute of NeuroscienceKey Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain ScienceSMMUShanghai200433China
| | - Ming Zhao
- Institute of NeuroscienceKey Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain ScienceSMMUShanghai200433China
| | - Dingya Sun
- Institute of NeuroscienceKey Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain ScienceSMMUShanghai200433China
| | - Zhenghua Xiang
- Institute of NeuroscienceKey Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain ScienceSMMUShanghai200433China
| | - Peng Liu
- Institute of NeuroscienceKey Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain ScienceSMMUShanghai200433China
| | - Yuqiang Ding
- Department of Laboratory Animal Scienceand State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceInstitutes of Brain ScienceFudan UniversityShanghai200032China
| | - Li Cao
- Institute of NeuroscienceKey Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain ScienceSMMUShanghai200433China
| | - Cheng He
- Institute of NeuroscienceKey Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain ScienceSMMUShanghai200433China
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21
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Pediatric ECMO: unfavorable outcomes are associated with inflammation and endothelial activation. Pediatr Res 2022; 92:549-556. [PMID: 34732815 PMCID: PMC9061896 DOI: 10.1038/s41390-021-01817-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 10/13/2021] [Accepted: 10/17/2021] [Indexed: 01/13/2023]
Abstract
BACKGROUND Inflammatory and endothelial activation responses during extracorporeal membrane oxygenation (ECMO) support in children are poorly understood. In this study, we aimed to determine if circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and with neurologic outcomes in children on ECMO. METHODS We conducted a secondary analysis of a two-center prospective observational study of 99 neonatal and pediatric ECMO patients. Inflammatory (interferon gamma [IFNγ], interleukin-6 [IL-6], IL-1β, tumor necrosis factor alpha [TNFα]), endothelial activation (E-selectin, P-selectin, intercellular adhesion molecule-3 [ICAM-3], thrombomodulin [TM]), and fibrinolytic markers (tissue plasminogen activator [tPA], plasminogen activator inhibitor-1 [PAI-1]) were measured in plasma on days 1, 2, 3, 5, 7, and every third day thereafter during the ECMO course. RESULTS All ECMO day 1 inflammatory biomarkers were significantly elevated in children with abnormal vs. normal neuroimaging. ECMO day 1 and peak levels of IL-6 and PAI-1 were significantly elevated in children who died compared to those who survived to hospital discharge. Tested biomarkers showed no significant association with long-term neurobehavioral outcomes measured using the Vineland Adaptive Behavioral Scales, Second Edition. CONCLUSIONS High levels of circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and abnormal neuroimaging in children on ECMO. IMPACT The inflammatory, endothelial activation, and fibrinolytic profile of children on ECMO differs by primary indication for extracorporeal support. Proinflammatory biomarkers on ECMO day 1 are associated with abnormal neurologic imaging in children on ECMO in univariable but not multivariable models. In multivariable models, a pronounced proinflammatory and prothrombotic biomarker profile on ECMO day 1 and longitudinally was significantly associated with mortality. Further studies are needed to identify inflammatory, endothelial, and fibrinolytic profiles associated with increased risk for neurologic injury and mortality through potential mediation of bleeding and thrombosis.
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22
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Favrais G, Bokobza C, Saliba E, Chalon S, Gressens P. Alteration of the Oligodendrocyte Lineage Varies According to the Systemic Inflammatory Stimulus in Animal Models That Mimic the Encephalopathy of Prematurity. Front Physiol 2022; 13:881674. [PMID: 35928559 PMCID: PMC9343871 DOI: 10.3389/fphys.2022.881674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/23/2022] [Indexed: 11/29/2022] Open
Abstract
Preterm birth before the gestational age of 32 weeks is associated with the occurrence of specific white matter damage (WMD) that can compromise the neurological outcome. These white matter abnormalities are embedded in more global brain damage defining the encephalopathy of prematurity (EoP). A global reduction in white matter volume that corresponds to chronic diffuse WMD is the most frequent form in contemporary cohorts of very preterm infants. This WMD partly results from alterations of the oligodendrocyte (OL) lineage during the vulnerability window preceding the beginning of brain myelination. The occurrence of prenatal, perinatal and postnatal events in addition to preterm birth is related to the intensity of WMD. Systemic inflammation is widely recognised as a risk factor of WMD in humans and in animal models. This review reports the OL lineage alterations associated with the WMD observed in infants suffering from EoP and emphasizes the role of systemic inflammation in inducing these alterations. This issue is addressed through data on human tissue and imaging, and through neonatal animal models that use systemic inflammation to induce WMD. Interestingly, the OL lineage damage varies according to the inflammatory stimulus, i.e., the liposaccharide portion of the E.Coli membrane (LPS) or the proinflammatory cytokine Interleukin-1β (IL-1β). This discrepancy reveals multiple cellular pathways inducible by inflammation that result in EoP. Variable long-term consequences on the white matter morphology and functioning may be speculated upon according to the intensity of the inflammatory challenge. This hypothesis emerges from this review and requires further exploration.
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Affiliation(s)
- Geraldine Favrais
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
- Neonatology Unit, CHRU de Tours, Tours, France
- *Correspondence: Geraldine Favrais,
| | - Cindy Bokobza
- Inserm, NeuroDiderot, Université Paris Cité, Paris, France
| | - Elie Saliba
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
| | - Sylvie Chalon
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
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23
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Ngo C, Kothary R. MicroRNAs in oligodendrocyte development and remyelination. J Neurochem 2022; 162:310-321. [PMID: 35536759 DOI: 10.1111/jnc.15618] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 03/14/2022] [Accepted: 04/20/2022] [Indexed: 11/28/2022]
Abstract
Oligodendrocytes are the glial cells responsible for the formation of myelin around axons of the central nervous system (CNS). Myelin is an insulating layer that allows electrical impulses to transmit quickly and efficiently along neurons. If myelin is damaged, as in chronic demyelinating disorders such as multiple sclerosis (MS), these impulses slow down. Remyelination by oligodendrocytes is often ineffective in MS, in part because of the failure of oligodendrocyte precursor cells (OPCs) to differentiate into mature, myelinating oligodendrocytes. The process of oligodendrocyte differentiation is tightly controlled by several regulatory networks involving transcription factors, intracellular signaling pathways, and extrinsic cues. Understanding the factors that regulate oligodendrocyte development is essential for the discovery of new therapeutic strategies capable of enhancing remyelination. Over the past decade, microRNAs (miRNAs) have emerged as key regulators of oligodendrocyte development, exerting effects on cell specification, proliferation, differentiation, and myelination. This article will review the role of miRNAs on oligodendrocyte biology and discuss their potential as promising therapeutic tools for remyelination.
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Affiliation(s)
- Clarissa Ngo
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Program in Biomedical Sciences, Faculty of Science, University of Ottawa, Ottawa, Ontario, Canada
| | - Rashmi Kothary
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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24
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Creswell R, Dombrowski Y. Innate and adaptive immune mechanisms regulating central nervous system remyelination. Curr Opin Pharmacol 2022; 63:102175. [DOI: 10.1016/j.coph.2021.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 11/03/2022]
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25
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Neuronal alarmin IL-1α evokes astrocyte-mediated protective signals: Effectiveness in chemotherapy-induced neuropathic pain. Neurobiol Dis 2022; 168:105716. [PMID: 35367629 DOI: 10.1016/j.nbd.2022.105716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 03/03/2022] [Accepted: 03/28/2022] [Indexed: 12/24/2022] Open
Abstract
The distinction between glial painful and protective pathways is unclear and the possibility to finely modulate the system is lacking. Focusing on painful neuropathies, we studied the role of interleukin 1α (IL-1α), an alarmin belonging to the larger family of damage-associated molecular patterns endogenously secreted to restore homeostasis. The treatment of rat primary neurons with increasing dose of the neurotoxic anticancer drug oxaliplatin (0.3-100μM, 48 h) induced the release of IL-1α. The knockdown of the alarmin in neurons leads to their higher mortality when co-cultured with astrocytes. This toxicity was related to increased extracellular ATP and decreased release of transforming growth factor β1, mostly produced by astrocytes. In a rat model of neuropathy induced by oxaliplatin, the intrathecal treatment with IL-1α was able to reduce mechanical and thermal hypersensitivity both after acute injection and continuous infusion. Ex vivo analysis on spinal purified astrocyte processes (gliosomes) and nerve terminals (synaptosomes) revealed the property of IL-1α to reduce the endogenous glutamate release induced by oxaliplatin. This protective effect paralleled with an increased number of GFAP-positive cells in the spinal cord, suggesting the ability of IL-1α to evoke a positive, conservative astrocyte phenotype. Endogenous IL-1α induces protective signals in the cross-talk between neurons and astrocytes. Exogenously administered in rats, IL-1α prevents neuropathic pain in the presence of spinal glutamate decrease and astrocyte activation.
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26
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Kimura Y, Hayashi Y, Hitomi S, Ikutame D, Urata K, Shibuta I, Sakai A, Ni J, Iwata K, Tonogi M, Shinoda M. IL-33 induces orofacial neuropathic pain through Fyn-dependent phosphorylation of GluN2B in the trigeminal spinal subnucleus caudalis. Brain Behav Immun 2022; 99:266-280. [PMID: 34715301 DOI: 10.1016/j.bbi.2021.10.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/14/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Orofacial neuropathic pain can cause considerable disruptions in patients' daily lives, especially because of a lack of effective medications as its underlying causative mechanisms are not fully understood. Here, we found neuron-specific expression of the interleukin (IL)-33 receptor in the trigeminal spinal subnucleus caudalis (Vc), distinct from the spinal dorsal horn. Reduction in head withdrawal threshold in response to von Frey filament stimulation of the whisker pad skin was inversely correlated with the upregulation of IL-33 in the Vc after infraorbital nerve injury (IONI). Neutralization of IL-33 in the Vc alleviated mechanical allodynia in the whisker pad skin after IONI; conversely, intracisternal administration of IL-33 elicited mechanical allodynia in the whisker pad skin, which was relieved by GluN2B antagonism. Moreover, IL-33 triggered the potentiation of GluN2B-containing N-methyl-D-aspartate receptor-mediated synaptic currents and phosphorylation of synaptosomal GluN2B in the Vc, whereas IONI-induced GluN2B phosphorylation was inhibited by neutralization of IL-33 in the Vc. IL-33-induced GluN2B phosphorylation was mediated by phosphorylation of Fyn kinase, and inhibition of the Fyn kinase pathway prevented the development of IL-33-induced mechanical allodynia. Our findings provide insights into a new mechanism by which IL-33 directly regulates synaptic transmission and suggest that IL-33 signaling could be a candidate target for therapeutic interventions for orofacial neuropathic pain.
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Affiliation(s)
- Yuki Kimura
- Department of Oral and Maxillofacial Surgery, Nihon University School of Dentistry, Tokyo, Japan
| | - Yoshinori Hayashi
- Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan.
| | - Suzuro Hitomi
- Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
| | - Daisuke Ikutame
- Department of Complete Denture Prosthodontics, Nihon University School of Dentistry, Tokyo, Japan
| | - Kentaro Urata
- Department of Complete Denture Prosthodontics, Nihon University School of Dentistry, Tokyo, Japan
| | - Ikuko Shibuta
- Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
| | - Atsushi Sakai
- Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Junjun Ni
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Koichi Iwata
- Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
| | - Morio Tonogi
- Department of Oral and Maxillofacial Surgery, Nihon University School of Dentistry, Tokyo, Japan
| | - Masamichi Shinoda
- Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
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27
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Poletti S, Mazza MG, Calesella F, Vai B, Lorenzi C, Manfredi E, Colombo C, Zanardi R, Benedetti F. Circulating inflammatory markers impact cognitive functions in bipolar depression. J Psychiatr Res 2021; 140:110-116. [PMID: 34107379 DOI: 10.1016/j.jpsychires.2021.05.071] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/05/2021] [Accepted: 05/29/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND Cognitive impairment is a core feature of bipolar disorder, with a prevalence of about 64.4% during episodes and 57.1% in euthymia. Recent evidences suggest that cognitive deficits in BD may follow immune dysfunction and elevated levels of inflammatory cytokines have been reported during periods of depression, mania and euthymia, suggesting the presence of a chronic, low-grade inflammatory state. The aim of the study is to investigate if immune/inflammatory markers and especially chemokines associate to cognitive performances. METHODS Seventy-six consecutively admitted inpatients with a depressive episode in course of bipolar disorder performed a neuropsychological evaluation with the Brief Assessment of Cognition in Schizophrenia and plasma blood levels of cytokines, chemokines and growth factors were analyzed with Luminex technology. RESULTS Higher levels of IL-1β, IL-6, CCL2, CCL4, CCL5, CXCL10, and bFGF are associated with the likelihood of having a poor cognitive performance. LIMITATIONS Limitation include the lack of a group of healthy controls and the lack of information regarding previous psychopharmacological treatments, alcohol and tobacco use. CONCLUSIONS Our results confirm the importance of chemokines in bipolar disorder and suggest that inflammatory markers suggestive of a low-grade inflammatory state could contribute to the neurocognitive deficits observed in depressed patients.
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Affiliation(s)
- Sara Poletti
- Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milano, Italy; University Vita-Salute San Raffaele, Milano, Italy.
| | - Mario Gennaio Mazza
- Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milano, Italy; University Vita-Salute San Raffaele, Milano, Italy
| | - Federico Calesella
- Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milano, Italy; University Vita-Salute San Raffaele, Milano, Italy
| | - Benedetta Vai
- Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milano, Italy; University Vita-Salute San Raffaele, Milano, Italy
| | - Cristina Lorenzi
- Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milano, Italy
| | - Elena Manfredi
- Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milano, Italy; University Vita-Salute San Raffaele, Milano, Italy
| | - Cristina Colombo
- Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milano, Italy; University Vita-Salute San Raffaele, Milano, Italy
| | - Raffaella Zanardi
- Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milano, Italy
| | - Francesco Benedetti
- Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milano, Italy; University Vita-Salute San Raffaele, Milano, Italy
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28
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Psenicka MW, Smith BC, Tinkey RA, Williams JL. Connecting Neuroinflammation and Neurodegeneration in Multiple Sclerosis: Are Oligodendrocyte Precursor Cells a Nexus of Disease? Front Cell Neurosci 2021; 15:654284. [PMID: 34234647 PMCID: PMC8255483 DOI: 10.3389/fncel.2021.654284] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 05/20/2021] [Indexed: 12/14/2022] Open
Abstract
The pathology in neurodegenerative diseases is often accompanied by inflammation. It is well-known that many cells within the central nervous system (CNS) also contribute to ongoing neuroinflammation, which can promote neurodegeneration. Multiple sclerosis (MS) is both an inflammatory and neurodegenerative disease in which there is a complex interplay between resident CNS cells to mediate myelin and axonal damage, and this communication network can vary depending on the subtype and chronicity of disease. Oligodendrocytes, the myelinating cell of the CNS, and their precursors, oligodendrocyte precursor cells (OPCs), are often thought of as the targets of autoimmune pathology during MS and in several animal models of MS; however, there is emerging evidence that OPCs actively contribute to inflammation that directly and indirectly contributes to neurodegeneration. Here we discuss several contributors to MS disease progression starting with lesion pathology and murine models amenable to studying particular aspects of disease. We then review how OPCs themselves can play an active role in promoting neuroinflammation and neurodegeneration, and how other resident CNS cells including microglia, astrocytes, and neurons can impact OPC function. Further, we outline the very complex and pleiotropic role(s) of several inflammatory cytokines and other secreted factors classically described as solely deleterious during MS and its animal models, but in fact, have many neuroprotective functions and promote a return to homeostasis, in part via modulation of OPC function. Finally, since MS affects patients from the onset of disease throughout their lifespan, we discuss the impact of aging on OPC function and CNS recovery. It is becoming clear that OPCs are not simply a bystander during MS progression and uncovering the active roles they play during different stages of disease will help uncover potential new avenues for therapeutic intervention.
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Affiliation(s)
- Morgan W. Psenicka
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Brandon C. Smith
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, United States
| | - Rachel A. Tinkey
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- School of Biomedical Sciences, Kent State University, Kent, OH, United States
| | - Jessica L. Williams
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- Brain Health Research Institute, Kent State University, Kent, OH, United States
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29
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Blandford SN, Galloway DA, Williams JB, Arsenault S, Brown J, MacLean G, Moore GRW, Barron J, Ploughman M, Clift F, Stefanelli M, Moore CS. Interleukin-1 receptor antagonist: An exploratory plasma biomarker that correlates with disability and provides pathophysiological insights in relapsing-remitting multiple sclerosis. Mult Scler Relat Disord 2021; 52:103006. [PMID: 34004435 DOI: 10.1016/j.msard.2021.103006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 04/13/2021] [Accepted: 04/29/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disorder. Interleukin-1 receptor antagonist (IL-1RA) is an endogenous soluble antagonist of the IL-1 receptor and blocks the pro-inflammatory effects of IL-1β known to contribute to MS pathology. The objectives of this study were to determine whether IL-1RA is associated with disability in MS and how this correlates with neurofilament light (NfL) levels in cerebrospinal fluid (CSF). METHODS Peripheral blood and CSF were collected from consenting MS patients. Patient demographic and clinical variables, including past relapse activity, were also collected. Circulating levels of IL-1RA, IL-18, and IL-1β were measured in plasma; IL-1RA and NfL were measured in the CSF via Bio-plex multiplex immunoassay kits and ELISA, respectively. IL-1RA expression was investigated in vitro using primary human macrophages and microglia, and in situ using post-mortem MS tissue. RESULTS Following a multiple regression analysis, IL-1RA levels in plasma correlated with expanded disability status scale score independent of all other variables. In a separate cohort, CSF IL-1RA significantly correlated with NfL. In vitro, induction of the NLRP3 inflammasome, a pathological hallmark within MS lesions, led to increased release of IL-1RA from primary human microglia and macrophages. In the CNS, IL-1RA+ macrophages/microglia were present at the rim of mixed active/inactive MS lesions. CONCLUSIONS Results presented in this study demonstrate that IL-1RA is a novel exploratory biomarker in relapsing-remitting MS, which correlates with disability and provides mechanistic insights into the regulatory inflammatory responses within the demyelinated CNS.
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Affiliation(s)
- Stephanie N Blandford
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, A1B 3V6 Newfoundland and Labrador, Canada
| | - Dylan A Galloway
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, A1B 3V6 Newfoundland and Labrador, Canada
| | - John B Williams
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, A1B 3V6 Newfoundland and Labrador, Canada
| | - Shane Arsenault
- Discipline of Medicine (Neurology), Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Janet Brown
- Discipline of Medicine (Neurology), Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Gregg MacLean
- Department of Medicine, Horizon Health, Saint John, New Brunswick, Canada
| | - G R Wayne Moore
- Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver British Columbia, Canada
| | - Jane Barron
- Discipline of Laboratory Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's Newfoundland and Labrador, Canada
| | - Michelle Ploughman
- Recovery and Performance Laboratory, Faculty of Medicine, Memorial University of Newfoundland, St. John's NL, Canada
| | - Fraser Clift
- Discipline of Medicine (Neurology), Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Mark Stefanelli
- Discipline of Medicine (Neurology), Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Craig S Moore
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, A1B 3V6 Newfoundland and Labrador, Canada; Discipline of Medicine (Neurology), Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
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30
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Hassanzadeh S, Jalessi M, Jameie SB, Khanmohammadi M, Bagher Z, Namjoo Z, Davachi SM. More attention on glial cells to have better recovery after spinal cord injury. Biochem Biophys Rep 2021; 25:100905. [PMID: 33553683 PMCID: PMC7844125 DOI: 10.1016/j.bbrep.2020.100905] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/29/2020] [Accepted: 12/29/2020] [Indexed: 01/01/2023] Open
Abstract
Functional improvement after spinal cord injury remains an unsolved difficulty. Glial scars, a major component of SCI lesions, are very effective in improving the rate of this recovery. Such scars are a result of complex interaction mechanisms involving three major cells, namely, astrocytes, oligodendrocytes, and microglia. In recent years, scientists have identified two subtypes of reactive astrocytes, namely, A1 astrocytes that induce the rapid death of neurons and oligodendrocytes, and A2 astrocytes that promote neuronal survival. Moreover, recent studies have suggested that the macrophage polarization state is more of a continuum between M1 and M2 macrophages. M1 macrophages that encourage the inflammation process kill their surrounding cells and inhibit cellular proliferation. In contrast, M2 macrophages promote cell proliferation, tissue growth, and regeneration. Furthermore, the ability of oligodendrocyte precursor cells to differentiate into adult oligodendrocytes or even neurons has been reviewed. Here, we first scrutinize recent findings on glial cell subtypes and their beneficial or detrimental effects after spinal cord injury. Second, we discuss how we may be able to help the functional recovery process after injury.
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Affiliation(s)
- Sajad Hassanzadeh
- Skull Base Research Center, Hazrat Rasoul Hospital, The Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran
- Neuroscience Research Center (NRC), Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Jalessi
- Skull Base Research Center, Hazrat Rasoul Hospital, The Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Behnamedin Jameie
- Neuroscience Research Center (NRC), Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Basic Sciences, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Khanmohammadi
- Skull Base Research Center, Hazrat Rasoul Hospital, The Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran
| | - Zohre Bagher
- ENT and Head & Neck Research Center and Department, The Five Senses Health Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Zeinab Namjoo
- Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Seyed Mohammad Davachi
- Department of Food Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, USA
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31
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Werkman IL, Kövilein J, de Jonge JC, Baron W. Impairing committed cholesterol biosynthesis in white matter astrocytes, but not grey matter astrocytes, enhances in vitro myelination. J Neurochem 2021; 156:624-641. [PMID: 32602556 PMCID: PMC7984098 DOI: 10.1111/jnc.15113] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/20/2020] [Accepted: 06/12/2020] [Indexed: 12/20/2022]
Abstract
Remyelination is a regenerative process that is essential to recover saltatory conduction and to prevent neurodegeneration upon demyelination. The formation of new myelin involves the differentiation of oligodendrocyte progenitor cells (OPCs) toward oligodendrocytes and requires high amounts of cholesterol. Astrocytes (ASTRs) modulate remyelination by supplying lipids to oligodendrocytes. Remarkably, remyelination is more efficient in grey matter (GM) than in white matter (WM), which may relate to regional differences in ASTR subtype. Here, we show that a feeding layer of gmASTRs was more supportive to in vitro myelination than a feeding layer of wmASTRs. While conditioned medium from both gmASTRs and wmASTRs accelerated gmOPC differentiation, wmOPC differentiation is enhanced by secreted factors from gmASTRs, but not wmASTRs. In vitro analyses revealed that gmASTRs secreted more cholesterol than wmASTRs. Cholesterol efflux from both ASTR types was reduced upon exposure to pro-inflammatory cytokines, which was mediated via cholesterol transporter ABCA1, but not ABCG1, and correlated with a minor reduction of myelin membrane formation by oligodendrocytes. Surprisingly, a wmASTR knockdown of Fdft1 encoding for squalene synthase (SQS), an enzyme essential for the first committed step in cholesterol biosynthesis, enhanced in vitro myelination. Reduced secretion of interleukin-1β likely by enhanced isoprenylation, and increased unsaturated fatty acid synthesis, both pathways upstream of SQS, likely masked the effect of reduced levels of ASTR-derived cholesterol. Hence, our findings indicate that gmASTRs export more cholesterol and are more supportive to myelination than wmASTRs, but specific inhibition of cholesterol biosynthesis in ASTRs is beneficial for wmASTR-mediated modulation of myelination.
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Affiliation(s)
- Inge L. Werkman
- Biomedical Sciences of Cells & Systemssection Molecular NeurobiologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
- Present address:
Department of BiologyUniversity of VirginiaCharlottesvilleVAUSA
| | - Janine Kövilein
- Biomedical Sciences of Cells & Systemssection Molecular NeurobiologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Jenny C. de Jonge
- Biomedical Sciences of Cells & Systemssection Molecular NeurobiologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Wia Baron
- Biomedical Sciences of Cells & Systemssection Molecular NeurobiologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
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32
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Boccazzi M, Van Steenwinckel J, Schang AL, Faivre V, Le Charpentier T, Bokobza C, Csaba Z, Verderio C, Fumagalli M, Mani S, Gressens P. The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation. Cell Death Dis 2021; 12:166. [PMID: 33558485 PMCID: PMC7870670 DOI: 10.1038/s41419-021-03446-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 12/13/2020] [Accepted: 01/03/2021] [Indexed: 12/20/2022]
Abstract
A leading cause of preterm birth is the exposure to systemic inflammation (maternal/fetal infection), which leads to neuroinflammation and white matter injury (WMI). A wide range of cytokines and chemokines are expressed and upregulated in oligodendrocytes (OLs) in response to inflammation and numerous reports show that OLs express several receptors for immune related molecules, which enable them to sense inflammation and to react. However, the role of OL immune response in WMI is unclear. Here, we focus our study on toll-like receptor-3 (TLR3) that is activated by double-strand RNA (dsRNA) and promotes neuroinflammation. Despite its importance, its expression and role in OLs remain unclear. We used an in vivo mouse model, which mimics inflammation-mediated WMI of preterm born infants consisting of intraperitoneal injection of IL-1β from P1 to P5. In the IL-1β-treated animals, we observed the upregulation of Tlr3, IL-1β, IFN-β, Ccl2, and Cxcl10 in both PDGFRα+ and O4+ sorted cells. This upregulation was higher in O4+ immature OLs (immOLs) as compared to PDGFRα+ OL precursor cells (OPCs), suggesting a different sensitivity to neuroinflammation. These observations were confirmed in OL primary cultures: cells treated with TLR3 agonist Poly(I:C) during differentiation showed a stronger upregulation of Ccl2 and Cxcl10 compared to cells treated during proliferation and led to decreased expression of myelin genes. Finally, OLs were able to modulate microglia phenotype and function depending on their maturation state as assessed by qPCR using validated markers for immunomodulatory, proinflammatory, and anti-inflammatory phenotypes and by phagocytosis and morphological analysis. These results show that during inflammation the response of OLs can play an autonomous role in blocking their own differentiation: in addition, the immune activation of OLs may play an important role in shaping the response of microglia during inflammation.
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Affiliation(s)
- Marta Boccazzi
- Université de Paris, Inserm UMR 1141 NeuroDiderot, F-75019, Paris, France.,PremUP, F-75006, Paris, France.,Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133, Milan, Italy
| | - Juliette Van Steenwinckel
- Université de Paris, Inserm UMR 1141 NeuroDiderot, F-75019, Paris, France.,PremUP, F-75006, Paris, France
| | - Anne-Laure Schang
- Université de Paris, Inserm UMR 1153, Centre de recherche en Epidémiologie et Statistiques (CRESS), Equipe HERA, Paris, France
| | - Valérie Faivre
- Université de Paris, Inserm UMR 1141 NeuroDiderot, F-75019, Paris, France.,PremUP, F-75006, Paris, France
| | - Tifenn Le Charpentier
- Université de Paris, Inserm UMR 1141 NeuroDiderot, F-75019, Paris, France.,PremUP, F-75006, Paris, France
| | - Cindy Bokobza
- Université de Paris, Inserm UMR 1141 NeuroDiderot, F-75019, Paris, France.,PremUP, F-75006, Paris, France
| | - Zsolt Csaba
- Université de Paris, Inserm UMR 1141 NeuroDiderot, F-75019, Paris, France.,PremUP, F-75006, Paris, France
| | - Claudia Verderio
- CNR Institute of Neuroscience, via Vanvitelli 32, 20129, Milan, Italy
| | - Marta Fumagalli
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133, Milan, Italy
| | - Shyamala Mani
- Université de Paris, Inserm UMR 1141 NeuroDiderot, F-75019, Paris, France.,PremUP, F-75006, Paris, France.,Curadev Pharma Pvt. Ltd, Noida, India
| | - Pierre Gressens
- Université de Paris, Inserm UMR 1141 NeuroDiderot, F-75019, Paris, France. .,PremUP, F-75006, Paris, France. .,Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, UK.
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33
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Bogie JFJ, Grajchen E, Wouters E, Corrales AG, Dierckx T, Vanherle S, Mailleux J, Gervois P, Wolfs E, Dehairs J, Van Broeckhoven J, Bowman AP, Lambrichts I, Gustafsson JÅ, Remaley AT, Mulder M, Swinnen JV, Haidar M, Ellis SR, Ntambi JM, Zelcer N, Hendriks JJA. Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain. J Exp Med 2020; 217:133840. [PMID: 32097464 PMCID: PMC7201924 DOI: 10.1084/jem.20191660] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 12/12/2019] [Accepted: 01/24/2020] [Indexed: 12/15/2022] Open
Abstract
Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination.
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Affiliation(s)
- Jeroen F J Bogie
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Elien Grajchen
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Elien Wouters
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Aida Garcia Corrales
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Tess Dierckx
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Sam Vanherle
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Jo Mailleux
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Pascal Gervois
- Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Esther Wolfs
- Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Jonas Dehairs
- Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven Cancer Institute, University of Leuven, Leuven, Belgium
| | - Jana Van Broeckhoven
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Andrew P Bowman
- The Maastricht MultiModal Molecular Imaging Institute, Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, Netherlands
| | - Ivo Lambrichts
- Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Jan-Åke Gustafsson
- Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX.,Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - Alan T Remaley
- Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Monique Mulder
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Johannes V Swinnen
- Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven Cancer Institute, University of Leuven, Leuven, Belgium
| | - Mansour Haidar
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Shane R Ellis
- The Maastricht MultiModal Molecular Imaging Institute, Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, Netherlands
| | - James M Ntambi
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI.,Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI
| | - Noam Zelcer
- Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Jerome J A Hendriks
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
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34
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Cellular senescence and failure of myelin repair in multiple sclerosis. Mech Ageing Dev 2020; 192:111366. [DOI: 10.1016/j.mad.2020.111366] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 08/10/2020] [Accepted: 09/23/2020] [Indexed: 01/10/2023]
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35
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Wagatsuma K, Nakase H. Contradictory Effects of NLRP3 Inflammasome Regulatory Mechanisms in Colitis. Int J Mol Sci 2020; 21:ijms21218145. [PMID: 33143375 PMCID: PMC7662299 DOI: 10.3390/ijms21218145] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 02/08/2023] Open
Abstract
The inflammasome is an intracellular molecular complex, which is mainly involved in innate immunity. Inflammasomes are formed in response to danger signals, associated with infection and injury, and mainly regulate the secretion of interleukin-1β and interleukin-18. Inflammasome dysregulation is known to be associated with various diseases and conditions, and its regulatory mechanisms have become of great interest in recent years. In the colon, inflammasomes have been reported to be associated with autophagy and the microbiota, and their dysregulation contributes to colitis and. However, the detailed role of inflammasomes in inflammatory bowel disease is still under debate because the mechanisms that regulate the inflammasome are complex and the inflammasome components and cytokines show seemingly contradictory multiple effects. Herein, we comprehensively review the literature on inflammasome functioning in the colon and describe the complex interactions of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome components with inflammatory cytokines, autophagy, and the microbiota in experimental colitis models and patients with inflammatory bowel disease.
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36
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Medved J, Wood WM, van Heyst MD, Sherafat A, Song JY, Sakya S, Wright DL, Nishiyama A. Novel guanidine compounds inhibit platelet-derived growth factor receptor alpha transcription and oligodendrocyte precursor cell proliferation. Glia 2020; 69:792-811. [PMID: 33098183 DOI: 10.1002/glia.23930] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 09/22/2020] [Accepted: 10/09/2020] [Indexed: 02/06/2023]
Abstract
Oligodendrocyte precursor cells (OPCs), also known as NG2 cells or polydendrocytes, are distributed widely throughout the developing and mature central nervous system. They remain proliferative throughout life and are an important source of myelinating cells in normal and demyelinating brain as well as a source of glioma, the most common type of primary brain tumor with a poor prognosis. OPC proliferation is dependent on signaling mediated by platelet-derived growth factor (PDGF) AA binding to its alpha receptor (PDGFRα). Here, we describe a group of structurally related compounds characterized by the presence of a basic guanidine group appended to an aromatic core that is effective in specifically repressing the transcription of Pdgfra but not the related beta receptor (Pdgfrb) in OPCs. These compounds specifically and dramatically reduced proliferation of OPCs but not that of astrocytes and did not affect signal transduction by PDGFRα. These findings suggest that the compounds could be further developed for potential use in combinatorial treatment strategies for neoplasms with dysregulated PDGFRα function.
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Affiliation(s)
- Jelena Medved
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA
| | - William M Wood
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA
| | - Michael D van Heyst
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Amin Sherafat
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA
| | - Ju-Young Song
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA.,Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Sagune Sakya
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA.,Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Dennis L Wright
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Akiko Nishiyama
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA.,Institute for Systems Genomics, University of Connecticut, Mansfield, Connecticut, USA.,Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, Mansfield, Connecticut, USA
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Furutama D, Matsuda S, Yamawaki Y, Hatano S, Okanobu A, Memida T, Oue H, Fujita T, Ouhara K, Kajiya M, Mizuno N, Kanematsu T, Tsuga K, Kurihara H. IL-6 Induced by Periodontal Inflammation Causes Neuroinflammation and Disrupts the Blood-Brain Barrier. Brain Sci 2020; 10:brainsci10100679. [PMID: 32992470 PMCID: PMC7599694 DOI: 10.3390/brainsci10100679] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/10/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023] Open
Abstract
Background: Periodontal disease (PD) is a risk factor for systemic diseases, including neurodegenerative diseases. The role of the local and systemic inflammation induced by PD in neuroinflammation currently remains unclear. The present study investigated the involvement of periodontal inflammation in neuroinflammation and blood–brain barrier (BBB) disruption. Methods: To induce PD in mice (c57/BL6), a ligature was placed around the second maxillary molar. Periodontal, systemic, and neuroinflammation were assessed based on the inflammatory cytokine mRNA or protein levels using qPCR and ELISA. The BBB permeability was evaluated by the mRNA levels and protein levels of tight junction-related proteins in the hippocampus using qPCR and immunofluorescence. Dextran tracing in the hippocampus was also conducted to examine the role of periodontal inflammation in BBB disruption. Results: The TNF-α, IL-1β, and IL-6 levels markedly increased in gingival tissue 1 week after ligation. The IL-6 serum levels were also increased by ligature-induced PD. In the hippocampus, the IL-1β mRNA expression levels were significantly increased by ligature-induced PD through serum IL-6. The ligature-induced PD decreased the claudin 5 expression levels in the hippocampus, and the neutralization of IL-6 restored its levels. The extravascular 3-kDa dextran levels were increased by ligature-induced PD. Conclusions: These results suggest that the periodontal inflammation-induced expression of IL-6 is related to neuroinflammation and BBB disruption in the hippocampus, ultimately leading to cognitive impairment. Periodontal therapy may protect against neurodegenerative diseases.
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Affiliation(s)
- Daisuke Furutama
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Shinji Matsuda
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
- Correspondence: ; Tel.: +81-082-257-5663
| | - Yosuke Yamawaki
- Department of Advanced Pharmacology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku Fukuoka 815-8511, Japan;
| | - Saki Hatano
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Ai Okanobu
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Takumi Memida
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Hiroshi Oue
- Department of Advanced Prosthodontics, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (H.O.); (K.T.)
| | - Tsuyoshi Fujita
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Kazuhisa Ouhara
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Mikihito Kajiya
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Noriyoshi Mizuno
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Takashi Kanematsu
- Laboratory of Cell Biology and Pharmacology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan;
| | - Kazuhiro Tsuga
- Department of Advanced Prosthodontics, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (H.O.); (K.T.)
| | - Hidemi Kurihara
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
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IRF5 Signaling in Phagocytes Is Detrimental to Neonatal Hypoxic Ischemic Encephalopathy. Transl Stroke Res 2020; 12:602-614. [PMID: 32761315 DOI: 10.1007/s12975-020-00832-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 06/10/2020] [Accepted: 07/01/2020] [Indexed: 01/20/2023]
Abstract
Immune responses to neonatal hypoxic ischemic encephalopathy (HIE) exacerbate brain injury. Phagocytes, including microglia, play a central role in the immune response, but how the activation of phagocytes is regulated remains elusive. Previously, we have reported that interferon regulatory factor 5 (IRF5) signaling is closely correlated with a pro-inflammatory microglial phenotype in adult mice after stroke. The present study investigated IRF5's regulatory role in post-HIE inflammation. Male IRF5 conditional knockout (CKO) and IRF5fl/fl postnatal day 10 (P10) pups were subjected to the Rice-Vannucci model (RVM) to induce HIE. Outcomes including morphological and neurobehavioral changes were evaluated at day 7 after HIE. Microglia/macrophage phenotypes and inflammatory responses were evaluated by flow cytometry (FC), RT-PCR, and multiplex cytokine assays. Lenti-IRF5 virus was administered in microglia-neuron co-cultures to evaluate the effects of microglial IRF5 upregulation in ischemic neurons exposed to oxygen-glucose deprivation (OGD). Deletion of phagocytic IRF5 resulted in significantly decreased IRF5 expression, attenuated pro-inflammatory and enhanced anti-inflammatory responses to HIE, and improved outcomes compared with IRF5fl/fl control pups. In vitro lentivirus transfection experiments revealed that overexpression of IRF5 in microglia amplified pro-inflammatory signals and exacerbated OGD-induced neuronal apoptosis and neurite fragmentation. IRF5 signaling mediates microglial pro-inflammatory activation and also affects anti-inflammatory responses. Phagocytic IRF5 signaling is detrimental in HIE and is a potential therapeutic target for post-ischemic inflammation.
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de Mol CL, Jansen PR, Muetzel RL, Knol MJ, Adams HH, Jaddoe VW, Vernooij MW, Hintzen RQ, White TJ, Neuteboom RF. Polygenic Multiple Sclerosis Risk and Population-Based Childhood Brain Imaging. Ann Neurol 2020; 87:774-787. [PMID: 32162725 PMCID: PMC7187244 DOI: 10.1002/ana.25717] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 03/10/2020] [Accepted: 03/10/2020] [Indexed: 11/20/2022]
Abstract
Objective Multiple sclerosis (MS) is a neurological disease with a substantial genetic component and immune‐mediated neurodegeneration. Patients with MS show structural brain differences relative to individuals without MS, including smaller regional volumes and alterations in white matter (WM) microstructure. Whether genetic risk for MS is associated with brain structure during early neurodevelopment remains unclear. In this study, we explore the association between MS polygenic risk scores (PRS) and brain imaging outcomes from a large, population‐based pediatric sample to gain insight into the underlying neurobiology of MS. Methods We included 8‐ to 12‐year‐old genotyped participants from the Generation R Study in whom T1‐weighted volumetric (n = 1,136) and/or diffusion tensor imaging (n = 1,088) had been collected. PRS for MS were calculated based on a large genome‐wide association study of MS (n = 41,505) and were regressed on regional volumes, global and tract‐specific fractional anisotropy (FA), and global mean diffusivity using linear regression. Results No associations were observed for the regional volumes. We observed a positive association between the MS PRS and global FA (β = 0.098, standard error [SE] = 0.030, p = 1.08 × 10−3). Tract‐specific analyses showed higher FA and lower radial diffusivity in several tracts. We replicated our findings in an independent sample of children (n = 186) who were scanned in an earlier phase (global FA; β = 0.189, SE = 0.072, p = 9.40 × 10−3). Interpretation This is the first study to show that greater genetic predisposition for MS is associated with higher global brain WM FA at an early age in the general population. Our results suggest a preadolescent time window within neurodevelopment in which MS risk variants act upon the brain. ANN NEUROL 2020;87:774–787
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Affiliation(s)
- C Louk de Mol
- Generation R Study Group, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Neurology, MS Center ErasMS, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Philip R Jansen
- Generation R Study Group, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Child and Adolescent Psychiatry, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, the Netherlands.,Department of Radiology and Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Clinical Genetics, VU Medical Center, Amsterdam, the Netherlands
| | - Ryan L Muetzel
- Generation R Study Group, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Child and Adolescent Psychiatry, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Maria J Knol
- Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Hieab H Adams
- Department of Radiology and Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Clinical Genetics, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Vincent W Jaddoe
- Generation R Study Group, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Pediatrics, Sophia Children's Hospital, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Meike W Vernooij
- Generation R Study Group, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Radiology and Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Rogier Q Hintzen
- Department of Neurology, MS Center ErasMS, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Tonya J White
- Department of Child and Adolescent Psychiatry, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Radiology and Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Rinze F Neuteboom
- Department of Neurology, MS Center ErasMS, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
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Extrinsic Factors Driving Oligodendrocyte Lineage Cell Progression in CNS Development and Injury. Neurochem Res 2020; 45:630-642. [PMID: 31997102 PMCID: PMC7058689 DOI: 10.1007/s11064-020-02967-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 12/19/2019] [Accepted: 12/21/2019] [Indexed: 12/15/2022]
Abstract
Oligodendrocytes (OLs) generate myelin membranes for the rapid propagation of electrical signals along axons in the central nervous system (CNS) and provide metabolites to support axonal integrity and function. Differentiation of OLs from oligodendrocyte progenitor cells (OPCs) is orchestrated by a multitude of intrinsic and extrinsic factors in the CNS. Disruption of this process, or OL loss in the developing or adult brain, as observed in various neurological conditions including hypoxia/ischemia, stroke, and demyelination, results in axonal dystrophy, neuronal dysfunction, and severe neurological impairments. While much is known regarding the intrinsic regulatory signals required for OL lineage cell progression in development, studies from pathological conditions highlight the importance of the CNS environment and external signals in regulating OL genesis and maturation. Here, we review the recent findings in OL biology in the context of the CNS physiological and pathological conditions, focusing on extrinsic factors that facilitate OL development and regeneration.
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Musella A, Fresegna D, Rizzo FR, Gentile A, De Vito F, Caioli S, Guadalupi L, Bruno A, Dolcetti E, Buttari F, Bullitta S, Vanni V, Centonze D, Mandolesi G. 'Prototypical' proinflammatory cytokine (IL-1) in multiple sclerosis: role in pathogenesis and therapeutic targeting. Expert Opin Ther Targets 2020; 24:37-46. [PMID: 31899994 DOI: 10.1080/14728222.2020.1709823] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: It has been recognized for about 20 years that interleukin (IL)-1 signaling is implicated in Multiple Sclerosis (MS), a disabling, chronic, inflammatory and neurodegenerative disease of the central nervous system (CNS). Only recently, multifaceted roles of IL-1 emerged in MS pathophysiology as a result of both clinical and preclinical studies. Notably, drugs that directly target the IL-1 system have not been tested so far in MS.Areas covered: Recent studies in animal models, together with the development of ex vivo chimeric MS models, have disclosed a critical role for IL-1 not only at the peripheral level but also within the CNS. In the present review, we highlight the IL-1-dependent neuropathological aspects of MS, by providing an overview of the cells of the immune and CNS systems that respond to IL-1 signaling, and by emphasizing the subsequent effects on the CNS, from demyelinating processes, to synaptopathy, and excitotoxicity.Expert opinion: Drugs that act on the IL-1 system show a therapeutic potential in several autoinflammatory diseases and preclinical studies have highlighted the effects of these compounds in MS. We will discuss why anti-IL-1 therapies in MS have been neglected to date.
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Affiliation(s)
- Alessandra Musella
- Synaptic Immunopathology Lab, IRCCS San Raffaele Pisana, Rome, Italy.,San Raffaele University, Rome, Italy
| | - Diego Fresegna
- Synaptic Immunopathology Lab, IRCCS San Raffaele Pisana, Rome, Italy
| | - Francesca Romana Rizzo
- Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, Rome, Italy
| | - Antonietta Gentile
- Synaptic Immunopathology Lab, IRCCS San Raffaele Pisana, Rome, Italy.,Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, Rome, Italy
| | | | - Silvia Caioli
- Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, Rome, Italy
| | - Livia Guadalupi
- Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, Rome, Italy
| | - Antonio Bruno
- Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, Rome, Italy
| | - Ettore Dolcetti
- Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, Rome, Italy
| | - Fabio Buttari
- Unit of Neurology, IRCCS Neuromed, Pozzilli, IS, Italy
| | - Silvia Bullitta
- Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, Rome, Italy
| | - Valentina Vanni
- Synaptic Immunopathology Lab, IRCCS San Raffaele Pisana, Rome, Italy
| | - Diego Centonze
- Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, Rome, Italy.,Unit of Neurology, IRCCS Neuromed, Pozzilli, IS, Italy
| | - Georgia Mandolesi
- Synaptic Immunopathology Lab, IRCCS San Raffaele Pisana, Rome, Italy.,San Raffaele University, Rome, Italy
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Xu Y, Fang Z, Wu C, Xu H, Kong J, Huang Q, Zhang H. The Long-Term Effects of Adolescent Social Defeat Stress on Oligodendrocyte Lineage Cells and Neuroinflammatory Mediators in Mice. Neuropsychiatr Dis Treat 2020; 16:1321-1330. [PMID: 32547035 PMCID: PMC7250299 DOI: 10.2147/ndt.s247497] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 04/30/2020] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Adverse childhood and adolescent experiences are associated with the emergences of psychopathology later in life and have negative consequences on white matter integrity. However, this adversity-induced white matter impairment remains not fully investigated. METHODS Adolescent Balb/c mice were subjected to intermittent social defeat stress once a day during postnatal days 25 to 40. Then, the subjects were allowed to recover for three weeks before sacrifice. At the end, oligodendrocyte (OL) lineage cells, cell proliferation, and microglia activation, as well as myelin basic protein (MBP) levels in frontal cortex and hippocampus were evaluated. The levels of interleukin (IL)-1β and IL-6 in the brain regions were assessed. RESULTS MBP protein level in frontal cortex, but not in the hippocampus of defeated mice, decreased significantly compared to controls. The numeral densities of mature OLs, oligodendrocyte progenitor cells, and proliferating cells in medial prefrontal cortex were comparable between the defeated mice and controls. The defeated mice, however, showed significantly higher IL-1β level, although IL-6 level and numeral density of microglia in frontal cortex did not change relative to controls. CONCLUSION These results indicate that effects of intermittent social defeat stress on the white matter integrity and OL lineage cells in mouse brain are region- and developmental stage-specific. Upregulated IL-1β may contribute to this negative consequence though the underlying mechanism remains to be investigated.
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Affiliation(s)
- Yingjuan Xu
- Shantou University Mental Health Center, Shantou, Guangdong, People's Republic of China
| | - Zeman Fang
- Shantou University Mental Health Center, Shantou, Guangdong, People's Republic of China
| | - Cairu Wu
- Shantou University Mental Health Center, Shantou, Guangdong, People's Republic of China
| | - Haiyun Xu
- Shantou University Mental Health Center, Shantou, Guangdong, People's Republic of China.,Affiliated Kangning Hospital, School of Psychiatry, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Jiming Kong
- Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB, Canada
| | - Qingjun Huang
- Shantou University Mental Health Center, Shantou, Guangdong, People's Republic of China
| | - Handi Zhang
- Shantou University Mental Health Center, Shantou, Guangdong, People's Republic of China
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43
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Pang J, Urao N, Koh TJ. Proliferation of Ly6C+ monocytes/macrophages contributes to their accumulation in mouse skin wounds. J Leukoc Biol 2019; 107:551-560. [PMID: 31777992 DOI: 10.1002/jlb.3hi1119-389rrrr] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/31/2019] [Accepted: 11/06/2019] [Indexed: 12/13/2022] Open
Abstract
Monocytes and macrophages (Mo/MΦ) play critical roles in all phases of skin wound healing. The majority of these cells are thought to be recruited from blood Mo; however, the role local proliferation of Mo/MΦ in the wound has not been defined. Therefore, we tested the hypothesis that local proliferation of Mo and/or MΦ contributes to their accumulation during wound healing. Male C57Bl/6 mice (N = 4-9/group) were subjected to excisional skin wounding. Proliferating Mo/MΦ (F4/80+Ki67+) were observed in wound cryosections, peaking on day 5 post-wounding. Cell cycle analysis on cells isolated from skin tissue revealed that wounding increased both the number and percentage of inflammatory Ly6C+F4/80lo/- Mo/MΦ in the S/G2/M phases, peaking on day 6 post-wounding. In contrast, more mature Ly6C-F4/80+ cells were found predominantly in the G0 phase with less than 1% cells in S/G2/M phase following injury. In peripheral blood, Mo were very rarely found in the S/G2/M phase, suggesting that the wound environment triggered the Ly6C+F4/80lo/- Mo proliferative response. Furthermore, injury induced several potential regulators of proliferation in wounds, including IL-1β and IL-6, and wound Mo/MΦ expressed surface receptors for these cytokines. However, wound Mo/MΦ proliferation was not altered in IL-1R1 knockout (KO) or IL-6 KO mice. In summary, our findings indicate that proliferation contributes to Mo/MΦ accumulation in wounds and, contrary to findings in other pathophysiologic conditions, Ly6C+/F4/80lo/- Mo/MΦ proliferate during skin wound healing whereas mature Ly6C-F4/80+ MΦ do not.
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Affiliation(s)
- Jingbo Pang
- Department of Kinesiology and Nutrition, Center for Wound Healing and Tissue Regeneration, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Norifumi Urao
- Department of Kinesiology and Nutrition, Center for Wound Healing and Tissue Regeneration, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Timothy J Koh
- Department of Kinesiology and Nutrition, Center for Wound Healing and Tissue Regeneration, University of Illinois at Chicago, Chicago, Illinois, USA
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44
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de Vivo L, Bellesi M. The role of sleep and wakefulness in myelin plasticity. Glia 2019; 67:2142-2152. [PMID: 31237382 PMCID: PMC6771952 DOI: 10.1002/glia.23667] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 06/07/2019] [Accepted: 06/11/2019] [Indexed: 12/17/2022]
Abstract
Myelin plasticity is gaining increasing recognition as an essential partner to synaptic plasticity, which mediates experience-dependent brain structure and function. However, how neural activity induces adaptive myelination and which mechanisms are involved remain open questions. More than two decades of transcriptomic studies in rodents have revealed that hundreds of brain transcripts change their expression in relation to the sleep-wake cycle. These studies consistently report upregulation of myelin-related genes during sleep, suggesting that sleep represents a window of opportunity during which myelination occurs. In this review, we summarize recent molecular and morphological studies detailing the dependence of myelin dynamics after sleep, wake, and chronic sleep loss, a condition that can affect myelin substantially. We present novel data about the effects of sleep loss on the node of Ranvier length and provide a hypothetical mechanism through which myelin changes in response to sleep loss. Finally, we discuss the current findings in humans, which appear to confirm the important role of sleep in promoting white matter integrity.
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Affiliation(s)
- Luisa de Vivo
- School of Physiology, Pharmacology and NeuroscienceUniversity of BristolBristolUK
| | - Michele Bellesi
- School of Physiology, Pharmacology and NeuroscienceUniversity of BristolBristolUK
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45
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Pfalzer AC, Crott JW, Koh GY, Smith DE, Garcia PE, Mason JB. Interleukin-1 Signaling Mediates Obesity-Promoted Elevations in Inflammatory Cytokines, Wnt Activation, and Epithelial Proliferation in the Mouse Colon. J Interferon Cytokine Res 2019; 38:445-451. [PMID: 30328795 DOI: 10.1089/jir.2017.0134] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Obesity is a prominent risk factor for colorectal cancer (CRC). One mechanism by which obesity promotes the development of CRC is by generating a chronic, low-grade state of colonic inflammation. Interleukin-1β (IL-1β), a proinflammatory cytokine often elevated in obesity, is known to activate several procarcinogenic signaling pathways that are implicated in colonic carcinogenesis. We therefore sought to define the role of IL-1β in mediating some of the early biochemical and molecular events leading up to obesity-promoted CRC. Twenty-five wild-type (WT) C57BL/6J mice and 24 lacking a functional IL-1 receptor (IL1R-/-) were each randomized to either low-fat or high-fat diets, resulting in lean and obese mice. Compared to WT lean controls, WT obese mice displayed 30%-80% greater concentrations of IL-1β and tumor necrosis factor-α (TNF-α) in the colonic mucosa (IL-1β: P = 0.04; TNF-α: P < 0.05), activation of the Wnt signaling cascade [evidenced by a 2-fold increase in colonic crypt cells displaying intranuclear β-catenin (P < 0.03)], and a significant expansion of the proliferation zone of the colonic crypt (P < 0.04). These obesity-induced alterations in colonic cytokines, Wnt signaling, and proliferation were absent in the obese IL1R-/- mice. In the absence of IL-1 signaling, obesity-induced elevations of colonic IL-1β, TNF-α, Wnt activation, and enhanced epithelial proliferation no longer occur. These observations underscore the important mechanistic roles that IL-1 signaling appears to play in mediating the procancerous effects of obesity in the colon, thereby identifying a potential target for future strategies aimed at chemoprevention.
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Affiliation(s)
- Anna C Pfalzer
- 1 Vitamins and Carcinogenesis Laboratory , Boston, Massachusetts.,2 Friedman School of Nutritional Science and Policy, Tufts University , Boston, Massachusetts
| | - Jimmy W Crott
- 1 Vitamins and Carcinogenesis Laboratory , Boston, Massachusetts.,2 Friedman School of Nutritional Science and Policy, Tufts University , Boston, Massachusetts
| | - Gar Yee Koh
- 1 Vitamins and Carcinogenesis Laboratory , Boston, Massachusetts.,2 Friedman School of Nutritional Science and Policy, Tufts University , Boston, Massachusetts
| | - Donald E Smith
- 3 Comparative Biology Unit, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University , Boston, Massachusetts
| | - Paloma E Garcia
- 1 Vitamins and Carcinogenesis Laboratory , Boston, Massachusetts
| | - Joel B Mason
- 1 Vitamins and Carcinogenesis Laboratory , Boston, Massachusetts.,2 Friedman School of Nutritional Science and Policy, Tufts University , Boston, Massachusetts.,4 Department of Gastroenterology, Tufts University School of Medicine , Boston, Massachusetts
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46
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Espitia Pinzon N, van Mierlo H, de Jonge JC, Brevé JJP, Bol JGJM, Drukarch B, van Dam AM, Baron W. Tissue Transglutaminase Promotes Early Differentiation of Oligodendrocyte Progenitor Cells. Front Cell Neurosci 2019; 13:281. [PMID: 31312122 PMCID: PMC6614186 DOI: 10.3389/fncel.2019.00281] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 06/11/2019] [Indexed: 01/09/2023] Open
Abstract
Demyelinated lesions of the central nervous system are characteristic for multiple sclerosis (MS). Remyelination is not very effective, particular at later stages of the disease, which results in a chronic neurodegenerative character with worsening of symptoms. Previously, we have shown that the enzyme Tissue Transglutaminase (TG2) is downregulated upon differentiation of oligodendrocyte progenitor cells (OPCs) into myelin-forming oligodendrocytes and that TG2 knock-out mice lag behind in remyelination after cuprizone-induced demyelination. Here, we examined whether astrocytic or oligodendroglial TG2 affects OPCs in a cell-specific manner to modulate their differentiation, and therefore myelination. Our findings indicate that human TG2-expressing astrocytes did not modulate OPC differentiation and myelination. In contrast, persistent TG2 expression upon OPC maturation or exogenously added recombinant TG2 accelerated OPC differentiation and myelin membrane formation. Continuous exposure of recombinant TG2 to OPCs at different consecutive developmental stages, however, decreased OPC differentiation and myelin membrane formation, while it enhanced myelination in dorsal root ganglion neuron-OPC co-cultures. In MS lesions, TG2 is absent in OPCs, while human OPCs show TG2 immunoreactivity during brain development. Exposure to the MS-relevant pro-inflammatory cytokine IFN-γ increased TG2 expression in OPCs and prolonged expression of endogenous TG2 upon differentiation. However, despite the increased TG2 levels, OPC maturation was not accelerated, indicating that TG2-mediated OPC differentiation may be counteracted by other pathways. Together, our data show that TG2, either endogenously expressed, or exogenously supplied to OPCs, accelerates early OPC differentiation. A better understanding of the role of TG2 in the OPC differentiation process during MS is of therapeutic interest to overcome remyelination failure.
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Affiliation(s)
- Nathaly Espitia Pinzon
- Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
| | - Hanneke van Mierlo
- Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Jenny C de Jonge
- Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - John J P Brevé
- Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
| | - John G J M Bol
- Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
| | - Benjamin Drukarch
- Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
| | - Anne-Marie van Dam
- Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
| | - Wia Baron
- Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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47
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Orozco Morales ML, Marsit NM, McIntosh OD, Hopkinson A, Sidney LE. Anti-inflammatory potential of human corneal stroma-derived stem cells determined by a novel in vitro corneal epithelial injury model. World J Stem Cells 2019; 11:84-99. [PMID: 30842807 PMCID: PMC6397805 DOI: 10.4252/wjsc.v11.i2.84] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 11/01/2018] [Accepted: 01/01/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND An in vitro injury model mimicking a corneal surface injury was optimised using human corneal epithelial cells (hCEC). AIM To investigate whether corneal-stroma derived stem cells (CSSC) seeded on an amniotic membrane (AM) construct manifests an anti-inflammatory, healing response. METHODS Treatment of hCEC with ethanol and pro-inflammatory cytokines were compared in terms of viability loss, cytotoxicity, and pro-inflammatory cytokine release, in order to generate the in vitro injury. This resulted in an optimal injury of 20% (v/v) ethanol for 30 s with 1 ng/mL interleukin-1 (IL-1) beta. Co-culture experiments were performed with CSSC alone and with CSSC-AM constructs. The effect of injury and co-culture on viability, cytotoxicity, IL-6 and IL-8 production, and IL1B, TNF, IL6, and CXCL8 mRNA expression were assessed. RESULTS Co-culture with CSSC inhibited loss of hCEC viability caused by injury. Enzyme linked immunosorbent assay and polymerase chain reaction showed a significant reduction in the production of IL-6 and IL-8 pro-inflammatory cytokines, and reduction in pro-inflammatory cytokine mRNA expression during co-culture with CSSC alone and with the AM construct. These results confirmed the therapeutic potential of the CSSC and the possible use of AM as a cell carrier for application to the ocular surface. CONCLUSION CSSC were shown to have a potentially therapeutic anti-inflammatory effect when treating injured hCEC, demonstrating an important role in corneal regeneration and wound healing, leading to an improved knowledge of their potential use for research and therapeutic purposes.
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Affiliation(s)
- Mariana Lizeth Orozco Morales
- Academic Ophthalmology, Division of Clinical Neuroscience, University of Nottingham, Nottingham, NG7 2UH, United Kingdom
| | - Nagi M Marsit
- Academic Ophthalmology, Division of Clinical Neuroscience, University of Nottingham, Nottingham, NG7 2UH, United Kingdom
| | - Owen D McIntosh
- Academic Ophthalmology, Division of Clinical Neuroscience, University of Nottingham, Nottingham, NG7 2UH, United Kingdom
| | - Andrew Hopkinson
- Academic Ophthalmology, Division of Clinical Neuroscience, University of Nottingham, Nottingham, NG7 2UH, United Kingdom
| | - Laura E Sidney
- Academic Ophthalmology, Division of Clinical Neuroscience, University of Nottingham, Nottingham, NG7 2UH, United Kingdom.
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48
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Neuroinflammation in preterm babies and autism spectrum disorders. Pediatr Res 2019; 85:155-165. [PMID: 30446768 DOI: 10.1038/s41390-018-0208-4] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 09/25/2018] [Accepted: 09/25/2018] [Indexed: 12/23/2022]
Abstract
Genetic anomalies have a role in autism spectrum disorders (ASD). Each genetic factor is responsible for a small fraction of cases. Environment factors, like preterm delivery, have an important role in ASD. Preterm infants have a 10-fold higher risk of developing ASD. Preterm birth is often associated with maternal/fetal inflammation, leading to a fetal/neonatal inflammatory syndrome. There are demonstrated experimental links between fetal inflammation and the later development of behavioral symptoms consistent with ASD. Preterm infants have deficits in connectivity. Most ASD genes encode synaptic proteins, suggesting that ASD are connectivity pathologies. Microglia are essential for normal synaptogenesis. Microglia are diverted from homeostatic functions towards inflammatory phenotypes during perinatal inflammation, impairing synaptogenesis. Preterm infants with ASD have a different phenotype from term born peers. Our original hypothesis is that exposure to inflammation in preterm infants, combined with at risk genetic background, deregulates brain development leading to ASD.
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49
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Erickson EK, Grantham EK, Warden AS, Harris RA. Neuroimmune signaling in alcohol use disorder. Pharmacol Biochem Behav 2018; 177:34-60. [PMID: 30590091 DOI: 10.1016/j.pbb.2018.12.007] [Citation(s) in RCA: 147] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 10/25/2018] [Accepted: 12/20/2018] [Indexed: 02/07/2023]
Abstract
Alcohol use disorder (AUD) is a widespread disease with limited treatment options. Targeting the neuroimmune system is a new avenue for developing or repurposing effective pharmacotherapies. Alcohol modulates innate immune signaling in different cell types in the brain by altering gene expression and the molecular pathways that regulate neuroinflammation. Chronic alcohol abuse may cause an imbalance in neuroimmune function, resulting in prolonged perturbations in brain function. Likewise, manipulating the neuroimmune system may change alcohol-related behaviors. Psychiatric disorders that are comorbid with AUD, such as post-traumatic stress disorder, major depressive disorder, and other substance use disorders, may also have underlying neuroimmune mechanisms; current evidence suggests that convergent immune pathways may be involved in AUD and in these comorbid disorders. In this review, we provide an overview of major neuroimmune cell-types and pathways involved in mediating alcohol behaviors, discuss potential mechanisms of alcohol-induced neuroimmune activation, and present recent clinical evidence for candidate immune-related drugs to treat AUD.
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Affiliation(s)
- Emma K Erickson
- Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712-01095, USA.
| | - Emily K Grantham
- Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712-01095, USA
| | - Anna S Warden
- Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712-01095, USA
| | - R A Harris
- Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712-01095, USA
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50
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Palomera LF, Gómez-Arauz AY, Villanueva-Ortega E, Meléndez-Mier G, Islas-Andrade SA, Escobedo G. Serum levels of interleukin-1 beta associate better with severity of simple steatosis than liver function tests in morbidly obese patients. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2018; 23:93. [PMID: 30505331 PMCID: PMC6225445 DOI: 10.4103/jrms.jrms_142_18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/05/2018] [Accepted: 07/17/2018] [Indexed: 12/21/2022]
Abstract
Background: In high-fat diet-fed mice, interleukin-1 beta (IL-1 beta) has been shown to play a key role in hepatic steatosis. However, it remains unknown whether IL-1 beta could be associated with different grades of steatosis in obese humans. Materials and Methods: Morbidly obese patients (n = 124) aged 18–65 years were divided into four groups: no steatosis (controls), mild steatosis, moderate steatosis, and severe steatosis using abdominal ultrasound. IL-1 beta serum levels and liver function tests were measured and significant differences were estimated by one-way ANOVA followed by Tukey test. Results: IL-1 beta serum levels significantly increased in morbidly obese patients with mild (11.38 ± 2.40 pg/ml), moderate (16.72 ± 2.47 pg/ml), and severe steatosis (23.29 ± 5.2 pg/ml) as compared to controls (7.78 ± 2.26 pg/ml). Liver function tests did not significantly change among different grades of steatosis. Conclusion: IL-1 beta serum levels associate better with steatosis degree than liver function tests in morbidly obese population.
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Affiliation(s)
- Leon F Palomera
- Research Division, Laboratory for Proteomics and Metabolomics, General Hospital of Mexico "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - Angélica Y Gómez-Arauz
- Research Division, Laboratory for Proteomics and Metabolomics, General Hospital of Mexico "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - Eréndira Villanueva-Ortega
- Department of Genetics, Clinic for Obesity, General Hospital of Mexico "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - Guillermo Meléndez-Mier
- Research Division, Laboratory for Proteomics and Metabolomics, General Hospital of Mexico "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - Sergio A Islas-Andrade
- Research Division, Laboratory for Proteomics and Metabolomics, General Hospital of Mexico "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - Galileo Escobedo
- Research Division, Laboratory for Proteomics and Metabolomics, General Hospital of Mexico "Dr. Eduardo Liceaga", Mexico City, Mexico
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