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Heneka MT, van der Flier WM, Jessen F, Hoozemanns J, Thal DR, Boche D, Brosseron F, Teunissen C, Zetterberg H, Jacobs AH, Edison P, Ramirez A, Cruchaga C, Lambert JC, Laza AR, Sanchez-Mut JV, Fischer A, Castro-Gomez S, Stein TD, Kleineidam L, Wagner M, Neher JJ, Cunningham C, Singhrao SK, Prinz M, Glass CK, Schlachetzki JCM, Butovsky O, Kleemann K, De Jaeger PL, Scheiblich H, Brown GC, Landreth G, Moutinho M, Grutzendler J, Gomez-Nicola D, McManus RM, Andreasson K, Ising C, Karabag D, Baker DJ, Liddelow SA, Verkhratsky A, Tansey M, Monsonego A, Aigner L, Dorothée G, Nave KA, Simons M, Constantin G, Rosenzweig N, Pascual A, Petzold GC, Kipnis J, Venegas C, Colonna M, Walter J, Tenner AJ, O'Banion MK, Steinert JR, Feinstein DL, Sastre M, Bhaskar K, Hong S, Schafer DP, Golde T, Ransohoff RM, Morgan D, Breitner J, Mancuso R, Riechers SP. Neuroinflammation in Alzheimer disease. Nat Rev Immunol 2025; 25:321-352. [PMID: 39653749 DOI: 10.1038/s41577-024-01104-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2024] [Indexed: 02/20/2025]
Abstract
Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.
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Affiliation(s)
- Michael T Heneka
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette/Belvaux, Luxembourg.
| | - Wiesje M van der Flier
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
| | - Frank Jessen
- Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
| | - Jeroen Hoozemanns
- Department of Pathology, Amsterdam Neuroscience, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Dietmar Rudolf Thal
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium
- Laboratory for Neuropathology, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
- Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), Leuven, Belgium
| | - Delphine Boche
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | | | - Charlotte Teunissen
- Department of Laboratory Medicine, VUMC Amsterdam, Amsterdam, The Netherlands
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Andreas H Jacobs
- European Institute for Molecular Imaging, University of Münster, Münster, Germany
| | - Paul Edison
- Division of Neurology, Department of Brain Sciences, Imperial College London, London, UK
| | - Alfredo Ramirez
- Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
- Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Carlos Cruchaga
- Department of Psychiatry, Washington School of Medicine in St. Louis, St. Louis, MO, USA
| | - Jean-Charles Lambert
- Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France
| | - Agustin Ruiz Laza
- ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), Barcelona, Spain
| | - Jose Vicente Sanchez-Mut
- Instituto de Neurociencias, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas (UMH-CSIC), Alicante, Spain
| | - Andre Fischer
- Clinic for Psychiatry and Psychotherapy, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany
- Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Centre for Neurodegenerative Disease (DZNE), Göttingen, Germany
| | - Sergio Castro-Gomez
- Center for Neurology, Clinic of Parkinson, Sleep and Movement Disorders, University Hospital Bonn, University of Bonn, Bonn, Germany
- Institute of Physiology II, University Hospital Bonn, University of Bonn, Bonn, Germany
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Thor D Stein
- Boston University Alzheimer's Disease Research Center and CTE Center, Department of Pathology & Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Luca Kleineidam
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Michael Wagner
- Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Jonas J Neher
- Biomedical Center Munich, Biochemistry, Medical Faculty, LMU Munich, Munich, Germany
- Neuroimmunology and Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Colm Cunningham
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland
- Trinity College Institute of Neuroscience (TCIN), Trinity College Dublin, Dublin, Ireland
| | - Sim K Singhrao
- Brain and Behaviour Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK
| | - Marco Prinz
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany
- Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Christopher K Glass
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Johannes C M Schlachetzki
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
| | - Oleg Butovsky
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kilian Kleemann
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Philip L De Jaeger
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Hannah Scheiblich
- Center for Neurology, Clinic of Parkinson, Sleep and Movement Disorders, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Guy C Brown
- Deparment of Biochemistry, University of Cambridge, Cambridge, UK
| | - Gary Landreth
- School of Medicine, Indiana University, Indianapolis, IN, USA
| | - Miguel Moutinho
- School of Medicine, Indiana University, Indianapolis, IN, USA
| | - Jaime Grutzendler
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
- Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - Diego Gomez-Nicola
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Róisín M McManus
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Katrin Andreasson
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Christina Ising
- Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Deniz Karabag
- Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Darren J Baker
- Department of Paediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Shane A Liddelow
- Neuroscience Institute, NYU Grossman School of Medicine, New York City, NY, USA
- Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York City, NY, USA
- Department of Ophthalmology, NYU Grossman School of Medicine, New York City, NY, USA
| | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Malu Tansey
- College of Medicine, University of Florida, Gainsville, FL, USA
| | - Alon Monsonego
- Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Ludwig Aigner
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Guillaume Dorothée
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Hôpital Saint-Antoine, Paris, France
| | - Klaus-Armin Nave
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Mikael Simons
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
| | - Gabriela Constantin
- Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Neta Rosenzweig
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Alberto Pascual
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
| | - Gabor C Petzold
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Department of Vascular Neurology, University of Bonn, Bonn, Germany
| | - Jonathan Kipnis
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St. Louis, MO, USA
| | - Carmen Venegas
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette/Belvaux, Luxembourg
- Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain
- Instituto Biosanitario de Granada (ibs.Granada), Granada, Spain
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Jochen Walter
- Center of Neurology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Andrea J Tenner
- Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA, USA
- Department of Neurobiology and Behaviour, University of California Irvine, Irvine, CA, USA
- Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - M Kerry O'Banion
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA
- Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA
| | - Joern R Steinert
- Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK
| | - Douglas L Feinstein
- Department of NeuroAnesthesia, University of Illinois at Chicago, Chicago, IL, USA
| | - Magdalena Sastre
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
| | - Kiran Bhaskar
- Department of Molecular Genetics & Microbiology and Neurology, University of New Mexico, Albuquerque, NM, USA
| | - Soyon Hong
- UK Dementia Research Institute, Institute of Neurology, University College London, London, UK
| | - Dorothy P Schafer
- Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Todd Golde
- Department of Pharmacology and Chemical Biology, Emory Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA
- Department of Neurology, Emory Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA
| | | | - David Morgan
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - John Breitner
- Department of Psychiatry, McGill University Faculty of Medicine, Montreal, Québec, Canada
| | - Renzo Mancuso
- Microglia and Inflammation in Neurological Disorders (MIND) Lab, VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Sean-Patrick Riechers
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette/Belvaux, Luxembourg
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Kostic M, Zivkovic N, Cvetanovic A, Basic J, Stojanovic I. Dissecting the immune response of CD4 + T cells in Alzheimer's disease. Rev Neurosci 2025; 36:139-168. [PMID: 39238424 DOI: 10.1515/revneuro-2024-0090] [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: 07/04/2024] [Accepted: 08/18/2024] [Indexed: 09/07/2024]
Abstract
The formation of amyloid-β (Aβ) plaques is a neuropathological hallmark of Alzheimer's disease (AD), however, these pathological aggregates can also be found in the brains of cognitively unimpaired elderly population. In that context, individual variations in the Aβ-specific immune response could be key factors that determine the level of Aβ-induced neuroinflammation and thus the propensity to develop AD. CD4+ T cells are the cornerstone of the immune response that coordinate the effector functions of both adaptive and innate immunity. However, despite intensive research efforts, the precise role of these cells during AD pathogenesis is still not fully elucidated. Both pathogenic and beneficial effects have been observed in various animal models of AD, as well as in humans with AD. Although this functional duality of CD4+ T cells in AD can be simply attributed to the vast phenotype heterogeneity of this cell lineage, disease stage-specific effect have also been proposed. Therefore, in this review, we summarized the current understanding of the role of CD4+ T cells in the pathophysiology of AD, from the aspect of their antigen specificity, activation, and phenotype characteristics. Such knowledge is of practical importance as it paves the way for immunomodulation as a therapeutic option for AD treatment, given that currently available therapies have not yielded satisfactory results.
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Affiliation(s)
- Milos Kostic
- Department of Immunology, Medical Faculty of Nis, University of Nis, Blvd. dr Zorana Djindjica 81, Nis, 18000, Serbia
| | - Nikola Zivkovic
- Department of Pathology, Medical Faculty of Nis, University of Nis, Blvd. dr Zorana Djindjica 81, Nis, 18000, Serbia
| | - Ana Cvetanovic
- Department of Oncology, Medical Faculty of Nis, University of Nis, Blvd. dr Zorana Djindjica 81, Nis, 18000, Serbia
| | - Jelena Basic
- Department of Biochemistry, Medical Faculty of Nis, University of Nis, Blvd. dr Zorana Djindjica 81, Nis, 18000, Serbia
| | - Ivana Stojanovic
- Department of Biochemistry, Medical Faculty of Nis, University of Nis, Blvd. dr Zorana Djindjica 81, Nis, 18000, Serbia
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Abdelhamed HG, Hassan AA, Sakraan AA, Al-Deeb RT, Mousa DM, Aboul Ezz HS, Noor NA, Khadrawy YA, Radwan NM. Brain interleukins and Alzheimer's disease. Metab Brain Dis 2025; 40:116. [PMID: 39891777 PMCID: PMC11787210 DOI: 10.1007/s11011-025-01538-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/10/2025] [Indexed: 02/03/2025]
Abstract
The central nervous system (CNS) is immune-privileged by several immuno-modulators as interleukins (ILs). ILs are cytokines secreted by immune cells for cell-cell signaling communications and affect the functions of the CNS. ILs were reported to orchestrate different molecular and cellular mechanisms of both physiological and pathological events, through overproduction or over-expression of their receptors. They interact with numerous receptors mediating pro-inflammatory and/or anti-inflammatory actions. Interleukins have been implicated to participate in neurodegenerative diseases. They play a critical role in Alzheimer's disease (AD) pathology which is characterized by the over-production of pro-inflammatory ILs. These may aggravate neurodegeneration, in addition to their contribution to detrimental mechanisms as oxidative stress, and excitotoxicity. However, recent research on the relation between ILs and AD revealed major discrepancies. Most of the major ILs were shown to play both pro- and anti-inflammatory roles in different experimental settings and models. The interactions between different ILs through shared pathways also add to the difficulty of drawing solid conclusions. In addition, targeting the different ILs has not yielded consistent results. The repeated failures of therapeutic drugs in treating AD necessitate the search for novel agents targeting multiple mechanisms of the disease pathology. In this context, the understanding of interleukins and their roles throughout the disease progression and interaction with other systems in the brain may provide promising therapeutic targets for the prevention or treatment of AD.
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Affiliation(s)
- Heba G Abdelhamed
- Department of Zoology and Chemistry, Faculty of Science, Cairo University, Giza, Egypt
| | - Arwa A Hassan
- Faculty of Pharmacy & Pharmaceutical Industries, Sinai University, Sinai, Egypt
| | - Alaa A Sakraan
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | | | - Dalia M Mousa
- Department of Biotechnology, Faculty of Science, Cairo University, Giza, Egypt
| | - Heba S Aboul Ezz
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt.
| | - Neveen A Noor
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | - Yasser A Khadrawy
- Medical Physiology Department, Medical Research and Clinical Studies Institute, National Research Center, Giza, Egypt
| | - Nasr M Radwan
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
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Sheng F, Li M, Yu JM, Yang SY, Zou L, Yang GJ, Zhang LL. IL-33/ST2 axis in diverse diseases: regulatory mechanisms and therapeutic potential. Front Immunol 2025; 16:1533335. [PMID: 39925809 PMCID: PMC11802536 DOI: 10.3389/fimmu.2025.1533335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 01/02/2025] [Indexed: 02/11/2025] Open
Abstract
Interleukin-33 (IL-33) is a nuclear factor and member of the IL-1 cytokine family. IL-33 is mainly expressed by epithelial and endothelial cells and exerts its function through interaction with various immune cells, and binding to its receptor can form the IL-33/Suppression of tumorigenicity 2 (ST2) signaling pathway. While most cytokines are actively synthesized within cells, IL-33 is produced passively in response to tissue damage or cell necrosis, indicating its role as a signaling molecule following cellular infection, stress, or trauma. IL-33/ST2 signaling pathway has been proved to play diverse role in the pathological process of central nervous system disorders, cancer, fibrosis, autoimmune diseases, etc. Although research on the IL-33/ST2 signaling pathway has deepened recently, relevant treatment strategies have been proposed, and even targeted drugs are in the preclinical stage; further research on the effect of the IL-33/ST2 signaling pathway in different diseases is still necessary, to provide a clearer understanding of the different roles of IL-33/ST2 in disease progression and to develop new drugs and treatment strategies. Because IL-33/ST2 plays an important role in the occurrence and progression of diseases, the study of therapeutic drugs targeting this pathway is also necessary. This review focused on recent studies on the positive or negative role of IL-33/ST2 in different diseases, as well as the current related drugs targeting IL-33/ST2 in the preclinical and clinical stage. The mechanism of IL-33/ST2 in different diseases and its mediating effect on different immune cells have been summarized, as well as the antibody drugs targeting IL-33 or ST2, natural compounds with a mediating effect, and small molecule substances targeting relative pathway. We aim to provide new ideas and treatment strategies for IL-33/ST2-related drugs to treat different diseases.
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Affiliation(s)
- Feiya Sheng
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
| | - Mi Li
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Jia-Mei Yu
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Si-Yu Yang
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Liang Zou
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China
| | - Guan-Jun Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro−Products, Ningbo University, Ningbo, China
| | - Le-Le Zhang
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, Macao SAR, China
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Li C, Zhang X, Wang Y, Cheng L, Li C, Xiang Y. The role of IL-1 family of cytokines in the pathogenesis and therapy of Alzheimer's disease. Inflammopharmacology 2024:10.1007/s10787-024-01534-8. [PMID: 39126573 DOI: 10.1007/s10787-024-01534-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 07/08/2024] [Indexed: 08/12/2024]
Abstract
Alzheimer's disease (AD) is a progressive and irreversible neurological condition that occurs with age and poses a significant global public health concern, is distinguished by the degeneration of neurons and synapses in various regions of the brain. While the exact processes behind the neurodegeneration in AD are not completely known, it is now acknowledged that inflammation may have a significant impact on the beginning and advancement of AD neurodegeneration. The severity of many neurological illnesses can be influenced by the equilibrium between pro-inflammatory and anti-inflammatory mediators. The IL-1 family of cytokines is linked to innate immune responses, which are present in both acute inflammation and chronic inflammatory diseases. Research on the role of the IL-1 family in chronic neurological disease has been concentrated on AD. In this context, there is indirect evidence suggesting its involvement in the development of the disease. This review aims to provide a summary of the contribution of every IL-1 family member in AD pathogenesis, current immunotherapies in AD disease, and present treatment possibilities for either targeting or boosting these cytokines.
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Affiliation(s)
- ChangQing Li
- Department of Laboratory Medicine, Chengdu Eighth People's Hospital (Geriatric Hospital of Chengdu Medical College), Chengdu, 610000, Sichuan, China
| | - Xun Zhang
- Department of Laboratory Medicine, Chengdu Eighth People's Hospital (Geriatric Hospital of Chengdu Medical College), Chengdu, 610000, Sichuan, China
| | - Yunqian Wang
- Department of Laboratory Medicine, Chengdu Eighth People's Hospital (Geriatric Hospital of Chengdu Medical College), Chengdu, 610000, Sichuan, China
| | - Le Cheng
- Department of Laboratory Medicine, Chengdu Eighth People's Hospital (Geriatric Hospital of Chengdu Medical College), Chengdu, 610000, Sichuan, China
| | - ChangBao Li
- Urology Department, Huili People's Hospital, Huili615100, Guangyuan, Sichuan, China
| | - Yu Xiang
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Ho G, Lam L, Tran T, Wei J, Hashimoto M. Innate neuroimmunity across aging and neurodegeneration: a perspective from amyloidogenic evolvability. Front Cell Dev Biol 2024; 12:1430593. [PMID: 39071802 PMCID: PMC11272618 DOI: 10.3389/fcell.2024.1430593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 06/17/2024] [Indexed: 07/30/2024] Open
Abstract
In Alzheimer's Disease (AD), amyloidogenic proteins (APs), such as β-amyloid (Aβ) and tau, may act as alarmins/damage-associated molecular patterns (DAMPs) to stimulate neuroinflammation and cell death. Indeed, recent evidence suggests that brain-specific type 2 immune networks may be important in modulating amyloidogenicity and brain homeostasis. Central to this, components of innate neuroimmune signaling, particularly type 2 components, assume distinctly specialized roles in regulating immune homeostasis and brain function. Whereas balanced immune surveillance stems from normal type 2 brain immune function, appropriate microglial clearance of aggregated misfolded proteins and neurotrophic and synaptotrophic signaling, aberrant pro-inflammatory activity triggered by alarmins might disrupt this normal immune homeostasis with reduced microglial amyloid clearance, synaptic loss, and ultimately neurodegeneration. Furthermore, since increased inflammation may in turn cause neurodegeneration, it is predicted that AP aggregation and neuroinflammation could synergistically promote even more damage. The reasons for maintaining such adverse biological conditions which have not been weeded out during evolution remain unclear. Here, we discuss these issues from a viewpoint of amyloidogenic evolvability, namely, aEVO, a hypothetic view of an adaptation to environmental stress by AP aggregates. Speculatively, the interaction of AP aggregation and neuroinflammation for aEVO in reproduction, which is evolutionally beneficial, might become a co-activating relationship which promotes AD pathogenesis through antagonistic pleiotropy. If validated, simultaneously suppressing both AP aggregation and specific innate neuroinflammation could greatly increase therapeutic efficacy in AD. Overall, combining a better understanding of innate neuroimmunity in aging and disease with the aEVO hypothesis may help uncover novel mechanism of pathogenesis of AD, leading to improved diagnostics and treatments.
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Affiliation(s)
- Gilbert Ho
- PCND Neuroscience Research Institute, Poway, CA, United States
| | - Linh Lam
- PCND Neuroscience Research Institute, Poway, CA, United States
| | - Tony Tran
- PCND Neuroscience Research Institute, Poway, CA, United States
| | - Jianshe Wei
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng, China
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Chen Z, Balachandran YL, Chong WP, Chan KWY. Roles of Cytokines in Alzheimer's Disease. Int J Mol Sci 2024; 25:5803. [PMID: 38891990 PMCID: PMC11171747 DOI: 10.3390/ijms25115803] [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: 04/16/2024] [Revised: 05/18/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
The neuroimmune system is a collection of immune cells, cytokines, and the glymphatic system that plays a pivotal role in the pathogenesis and progression of Alzheimer's disease (AD). Of particular focus are cytokines, a group of immune signaling molecules that facilitate communication among immune cells and contribute to inflammation in AD. Extensive research has shown that the dysregulated secretion of certain cytokines (IL-1β, IL-17, IL-12, IL-23, IL-6, and TNF-α) promotes neuroinflammation and exacerbates neuronal damage in AD. However, anti-inflammatory cytokines (IL-2, IL-3, IL-33, and IL-35) are also secreted during AD onset and progression, thereby preventing neuroinflammation. This review summarizes the involvement of pro- and anti-inflammatory cytokines in AD pathology and discusses their therapeutic potential.
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Affiliation(s)
- Zilin Chen
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China; (Z.C.); (Y.L.B.)
| | - Yekkuni L. Balachandran
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China; (Z.C.); (Y.L.B.)
| | - Wai Po Chong
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
- Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen 518057, China
| | - Kannie W. Y. Chan
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China; (Z.C.); (Y.L.B.)
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Hong Kong Centre for Cerebro-Cardiovascular Health Engineering (COCHE), Hong Kong, China
- Shenzhen Research Institute, City University of Hong Kong Shenzhen Research Institute, Shenzhen 518057, China
- Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, China
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Wu J, Carlock C, Tatum K, Shim J, Zhou C, Lou Y. Activation of interleukin 33-NFκB axis in granulosa cells during atresia and its role in disposal of atretic follicles†. Biol Reprod 2024; 110:924-935. [PMID: 38271626 PMCID: PMC11094390 DOI: 10.1093/biolre/ioae015] [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: 01/13/2023] [Revised: 05/22/2023] [Accepted: 01/18/2024] [Indexed: 01/27/2024] Open
Abstract
It has been previously shown that the cytokine interleukin 33 is required for two processes, i.e., autophagic digestion of granulosa cells and recruitment of macrophages into atretic follicles, for full disposal of atretic follicles. Now, this study shows that activation of interleukin 33-suppression of tumorigenicity 2-Nuclear Factor ĸB (NFκB) axis in granulosa in early atretic follicles may regulate those two events. Injection of human chorionic gonadotropin has been shown to induce a transient peak of interleukin 33 expression with synchronized atresia. In this model, interleukin 33-independent expression of suppression of tumorigenicity 2 in granulosa cells was detected in early atretic follicles before macrophage invasion. The activation of NFκB pathway in ovaries was further demonstrated in vivo in Tg mice with luciferase-reporter for NFκB activation; the activation was microscopically localized to granulosa cells in early atretic follicles. Importantly, antibody blockage of interleukin 33 or interleukin 33 Knock-out (KO) (Il33-/-) not only inhibited NFκB activity in ovaries, but it also altered expression of two key genes, i.e., reduction in proinflammatory interleukin6 (IL6) expression, and a surge of potential autophagy-inhibitory mammalian target of rapamycin (mTOR) expression in atretic follicles. By contrast, apoptosis and other genes, such as interleukin1β (IL1β) were not affected. In conclusion, in parallel to apoptosis, atresia signals also trigger activation of the interleukin 33-suppression of tumorigenicity 2-NFκB pathway in granulosa, which leads to (1) down-regulated expression of mTOR that is a negative regulator of autophagy and (2) up-regulated expression of proinflammatory IL6.
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Affiliation(s)
- Jean Wu
- Department of Diagnostic Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Colin Carlock
- Department of Diagnostic Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Kiana Tatum
- Department of Diagnostic Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Junbo Shim
- Department of Diagnostic Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Cindy Zhou
- Department of Diagnostic Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yahuan Lou
- Department of Diagnostic Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
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9
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Matini M, Amini R, Foroughi-Parvar F. Glia Maturation Factor Beta: A Novel Neuro-Impairment Prediction Factor in Toxoplasmosis. IRANIAN JOURNAL OF PUBLIC HEALTH 2024; 53:1200-1208. [PMID: 38912132 PMCID: PMC11188646 DOI: 10.18502/ijph.v53i5.15602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/11/2023] [Indexed: 06/25/2024]
Abstract
Background Toxoplasma gondii, a neurotropic protozoan, infects up one to third of the world population. The parasite can invade a wide variety of nucleated cells but preferably glial cells. Glia maturation factor β (GMFβ), a 17KD protein expressed at high levels in the central nervous system is predominantly related to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Multiple sclerosis. We aimed to determine the expression level of GMFβ and its relation to other pro-inflammatory factors (IL33, SDF1, and CCL2) on T. gondii infected human neuroblastoma cell line. Methods The human neuroblastoma (SK_NMC C535) cell line was infected by 5×106 (1:1 ratio). The supernatant was collected after cell lysis and centrifugation. Total RNA was extracted using the Yekta Tajhiz RNA extraction kit. cDNA was synthesized based on RevertAid First Strand cDNA Synthesis Kit manufacturer's protocol (Parstous, cDNA synthesis kit, Iran). The specificity of each primer pair (GMFβ, IL33, SDF1, and CCL2) was provided by NCBI BLAST. Gene expression level was measured using Real-Time PCR. All experiments were conducted at the Hamadan University of Medical Sciences, western Iran in 2022. Results The GMFβ increased significantly up to 1.35-fold (P=0.007). The increase in GMFβ expression in neuroblastoma cells was consistent with the increase in pro-inflammatory factors (CCL2 (0.47), IL33 (0.152) and, SDF1 (1.33)). Conclusion GMFβ upregulation can be a novel indicator of the destruction of nerve cells.
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Affiliation(s)
- Mohammad Matini
- Department of Medical Parasitology and Mycology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Razieh Amini
- Department of Molecular Medicine and Human Genetics, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Faeze Foroughi-Parvar
- Department of Medical Parasitology and Mycology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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10
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Achiro JM, Tao Y, Gao F, Lin CH, Watanabe M, Neumann S, Coppola G, Black DL, Martin KC. Aging differentially alters the transcriptome and landscape of chromatin accessibility in the male and female mouse hippocampus. Front Mol Neurosci 2024; 17:1334862. [PMID: 38318533 PMCID: PMC10839115 DOI: 10.3389/fnmol.2024.1334862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/02/2024] [Indexed: 02/07/2024] Open
Abstract
Aging-related memory impairment and pathological memory disorders such as Alzheimer's disease differ between males and females, and yet little is known about how aging-related changes in the transcriptome and chromatin environment differ between sexes in the hippocampus. To investigate this question, we compared the chromatin accessibility landscape and gene expression/alternative splicing pattern of young adult and aged mouse hippocampus in both males and females using ATAC-seq and RNA-seq. We detected significant aging-dependent changes in the expression of genes involved in immune response and synaptic function and aging-dependent changes in the alternative splicing of myelin sheath genes. We found significant sex-bias in the expression and alternative splicing of hundreds of genes, including aging-dependent female-biased expression of myelin sheath genes and aging-dependent male-biased expression of genes involved in synaptic function. Aging was associated with increased chromatin accessibility in both male and female hippocampus, especially in repetitive elements, and with an increase in LINE-1 transcription. We detected significant sex-bias in chromatin accessibility in both autosomes and the X chromosome, with male-biased accessibility enriched at promoters and CpG-rich regions. Sex differences in gene expression and chromatin accessibility were amplified with aging, findings that may shed light on sex differences in aging-related and pathological memory loss.
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Affiliation(s)
- Jennifer M. Achiro
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
| | - Yang Tao
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
| | - Fuying Gao
- Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
| | - Chia-Ho Lin
- Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, United States
| | - Marika Watanabe
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
| | - Sylvia Neumann
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
| | - Giovanni Coppola
- Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
| | - Douglas L. Black
- Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, United States
| | - Kelsey C. Martin
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
- Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
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11
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Jia Z, Guo M, Ge X, Chen F, Lei P. IL-33/ST2 Axis: A Potential Therapeutic Target in Neurodegenerative Diseases. Biomolecules 2023; 13:1494. [PMID: 37892176 PMCID: PMC10605306 DOI: 10.3390/biom13101494] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/01/2023] [Accepted: 10/03/2023] [Indexed: 10/29/2023] Open
Abstract
Interleukin 33 (IL-33) belongs to the IL-1 family and is localized in the nucleus. IL-33 is primarily composed of three distinct domains, namely the N-terminal domain responsible for nuclear localization, the intermediate sense protease domain, and the C-terminal cytokine domain. Its specific receptor is the suppression of tumorigenicity 2 (ST2), which is detected in serum-stimulated fibroblasts and oncogenes. While most other cytokines are actively produced in cells, IL-33 is passively produced in response to tissue damage or cell necrosis, thereby suggesting its role as an alarm following cell infection, stress, or trauma. IL-33 plays a crucial role in congenital and acquired immunity, which assists in the response to environmental stress and maintains tissue homeostasis. IL-33/ST2 interaction further produces many pro-inflammatory cytokines. Moreover, IL-33 is crucial for central nervous system (CNS) homeostasis and the pathogenic mechanisms underlying CNS degenerative disorders. The present work summarizes the structure of IL-33, its fundamental activities, and its role in immunoregulation and neurodegenerative diseases. Therefore, this work proposes that IL-33 may play a role in the pathogenic mechanism of diseases and can be used in the development of treatment strategies.
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Affiliation(s)
- Zexi Jia
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China; (Z.J.); (X.G.)
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Mengtian Guo
- Department of Internal Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100054, China;
| | - Xintong Ge
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China; (Z.J.); (X.G.)
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Fanglian Chen
- Tianjin Neurological Institute, Tianjin 300052, China
| | - Ping Lei
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China; (Z.J.); (X.G.)
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
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12
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Carvalho D, Diaz-Amarilla P, Dapueto R, Santi MD, Duarte P, Savio E, Engler H, Abin-Carriquiry JA, Arredondo F. Transcriptomic Analyses of Neurotoxic Astrocytes Derived from Adult Triple Transgenic Alzheimer's Disease Mice. J Mol Neurosci 2023; 73:487-515. [PMID: 37318736 DOI: 10.1007/s12031-023-02105-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 02/03/2023] [Indexed: 06/16/2023]
Abstract
Neurodegenerative diseases such as Alzheimer's disease have been classically studied from a purely neuronocentric point of view. More recent evidences support the notion that other cell populations are involved in disease progression. In this sense, the possible pathogenic role of glial cells like astrocytes is increasingly being recognized. Once faced with tissue damage signals and other stimuli present in disease environments, astrocytes suffer many morphological and functional changes, a process referred as reactive astrogliosis. Studies from murine models and humans suggest that these complex and heterogeneous responses could manifest as disease-specific astrocyte phenotypes. Clear understanding of disease-associated astrocytes is a necessary step to fully disclose neurodegenerative processes, aiding in the design of new therapeutic and diagnostic strategies. In this work, we present the transcriptomics characterization of neurotoxic astrocytic cultures isolated from adult symptomatic animals of the triple transgenic mouse model of Alzheimer's disease (3xTg-AD). According to the observed profile, 3xTg-AD neurotoxic astrocytes show various reactivity features including alteration of the extracellular matrix and release of pro-inflammatory and proliferative factors that could result in harmful effects to neurons. Moreover, these alterations could be a consequence of stress responses at the endoplasmic reticulum and mitochondria as well as of concomitant metabolic adaptations. Present results support the hypothesis that adaptive changes of astrocytic function induced by a stressed microenvironment could later promote harmful astrocyte phenotypes and further accelerate or induce neurodegenerative processes.
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Affiliation(s)
- Diego Carvalho
- Departamento de Neuroquímica, Instituto de Investigaciones Biológicas Clemente Estable, 11600, Montevideo, Uruguay
| | - Pablo Diaz-Amarilla
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - Rosina Dapueto
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - María Daniela Santi
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
- College of Dentistry, Bluestone Center for Clinical Research, New York University, New York, 10010, USA
| | - Pablo Duarte
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - Eduardo Savio
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - Henry Engler
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
- Facultad de Medicina, Universidad de la República, 1800, Montevideo, Uruguay
| | - Juan A Abin-Carriquiry
- Departamento de Neuroquímica, Instituto de Investigaciones Biológicas Clemente Estable, 11600, Montevideo, Uruguay.
- Laboratorio de Biofármacos, Institut Pasteur de Montevideo, 11600, Montevideo, Uruguay.
| | - Florencia Arredondo
- Departamento de Neuroquímica, Instituto de Investigaciones Biológicas Clemente Estable, 11600, Montevideo, Uruguay.
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay.
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13
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Jiang T, Zheng T, Li W, Liu N, Wang M. IL-33/ST2 signaling pathway and Alzheimer's disease: A systematic review and meta-analysis. Clin Neurol Neurosurg 2023; 230:107773. [PMID: 37172376 DOI: 10.1016/j.clineuro.2023.107773] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/03/2023] [Accepted: 05/07/2023] [Indexed: 05/14/2023]
Abstract
The IL-33/ST2 signaling pathway has potential relevance for clinical identification and treatment of Alzheimer's disease (AD). Here, eight databases (including CNKI, Wanfang, SinoMed, VIP, PubMed, Cochrane library, Embase and Web of Science) were employed to search for studies on IL-33/ST2 signaling pathway and its association with AD. Totally, 15 articles were included, of which 5 studies investigated the connection between IL-33 gene polymorphisms and AD, 4 studies explored the serum IL-33 and sST2 levels in patients with AD and Mild cognitive impairment (MCI), and the exact mechanisms underlying IL-33/ST2 signaling pathway in AD were explored in 6 studies. Then, the RevMan 5.4 software was used for meta-analysis, and the related studies were systematically reviewed. The results of the meta-analysis showed that serum IL-33 levels were higher in patients with AD and MCI than in healthy controls (HC), with serum IL-33 levels in AD patients significantly higher than in MCI patients (SMD = 0.26, 95 % CI: 0.02, 0.51; P = 0.04). Compared with HC, the sST2 level was significantly higher in AD patients (SMD = 1.23, 95 % CI: 0.93, 1.53; P < 0.00001) and tended to elevate in patients with MCI. The systematic review indicated that there is a significant relationship between IL-33 gene polymorphisms and susceptibility to AD; The IL-33/ST2 signaling pathway may be one of the future treatment targets for AD. Our study provides evidence to prove that serum IL-33 and sST2 have potential clinical application value as biomarkers for identifying AD.
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Affiliation(s)
- Taotao Jiang
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Ting Zheng
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Wenhao Li
- Department of neurosurgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ning Liu
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Manxia Wang
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou 730030, China.
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14
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Tan YJ, Siow I, Saffari SE, Ting SKS, Li Z, Kandiah N, Tan LCS, Tan EK, Ng ASL. Plasma Soluble ST2 Levels Are Higher in Neurodegenerative Disorders and Associated with Poorer Cognition. J Alzheimers Dis 2023; 92:573-580. [PMID: 36776067 DOI: 10.3233/jad-221072] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
BACKGROUND Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases. OBJECTIVE To investigate plasma sST2 levels in controls and patients with MCI, AD, frontotemporal dementia (FTD), and Parkinson's disease (PD). METHODS Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed. RESULTS Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels. CONCLUSION Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration.
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Affiliation(s)
- Yi Jayne Tan
- Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore
| | - Isabel Siow
- Ministry of Health Holdings, Singapore, Singapore
| | - Seyed Ehsan Saffari
- Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore.,Center for Quantitative Medicine, Duke-NUS Medical School, National University of Singapore, Singapore
| | - Simon K S Ting
- Department of Neurology, Singapore General Hospital, Singapore
| | - Zeng Li
- Neural Stem Cell Research Lab, Department of Research, National Neuroscience Institute, Singapore
| | - Nagaendran Kandiah
- Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore
| | - Louis C S Tan
- Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore
| | - Eng King Tan
- Center for Quantitative Medicine, Duke-NUS Medical School, National University of Singapore, Singapore.,Neuroscience and Behavioural Disorders Unit, Duke-NUS Medical School, Singapore
| | - Adeline S L Ng
- Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore.,Neuroscience and Behavioural Disorders Unit, Duke-NUS Medical School, Singapore
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15
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Zamorano M, Alexander JF, Catania D, Dharmaraj S, Kavelaars A, Heijnen CJ. Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice. Immun Ageing 2023; 20:5. [PMID: 36698170 PMCID: PMC9874182 DOI: 10.1186/s12979-023-00328-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 01/12/2023] [Indexed: 01/26/2023]
Abstract
BACKGROUND There is increasing concern that cancer and cancer treatment accelerate aging and the associated cognitive decline. We showed recently that treatment of 9-month-old male mice with cisplatin causes cognitive deficits that are associated with formation of tau deposits in the hippocampus. Here we explored the capacity of mesenchymal stem cells (MSC) given via the nose to prevent age-related brain tau deposits. Moreover, we more closely examined the cellular distribution of this hallmark of accelerated brain aging in response to treatment of 9-month-old female and male mice with cisplatin. RESULTS We show that cisplatin induces tau deposits in the entorhinal cortex and hippocampus in both sexes. The tau deposits colocalize with syndecan-2. Astrocytes surrounding tau deposits have increased glial fibrillary acidic protein glial fibrillary acidic protein (GFAP) expression. Most of the cisplatin-induced tau deposits were located in microtubule associated protein-2 (MAP-2)+ neurons that were surrounded by aquaporin 4+ (AQP4)+ neuron-facing membrane domains of astrocytes. In addition, some tau deposits were detected in the perinuclear region of GFAP+ astrocytes and in CD31+ endothelial cells. There were no morphological signs of activation of ionized calcium binding adaptor molecule-1+ (Iba-1)+ microglia and no increases in brain cytokine production. Nasal administration of MSC at 48 and 96 hours after cisplatin prevented formation of tau deposits and normalized syndecan-2 and GFAP expression. Behaviorally, cisplatin-induced tau cluster formation was associated with reduced executive functioning and working/spatial memory and nasal administration of MSC at 48 and 96 hours after cisplatin prevented these cognitive deficits. Notably, delayed MSC administration (1 month after cisplatin) also prevented tau cluster formation and cognitive deficits, in both sexes. CONCLUSION In summary, nasal administration of MSC to older mice at 2 days or 1 month after completion of cisplatin treatment prevents the accelerated development of tau deposits in entorhinal cortex and hippocampus and the associated cognitive deficits. Since MSC are already in clinical use for many other clinical indications, developing nasal MSC administration for treatment of accelerated brain aging and cognitive deficits in cancer survivors should be feasible and would greatly improve their quality of life.
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Affiliation(s)
- Miriam Zamorano
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA ,grid.267308.80000 0000 9206 2401Department of Pediatric Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX USA
| | - Jenolyn F. Alexander
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA ,grid.410718.b0000 0001 0262 7331Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr, 55 Essen, Germany
| | - Desiree Catania
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA
| | - Shruti Dharmaraj
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA
| | - Annemieke Kavelaars
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA
| | - Cobi J. Heijnen
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA
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16
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Rao X, Hua F, Zhang L, Lin Y, Fang P, Chen S, Ying J, Wang X. Dual roles of interleukin-33 in cognitive function by regulating central nervous system inflammation. J Transl Med 2022; 20:369. [PMID: 35974336 PMCID: PMC9382782 DOI: 10.1186/s12967-022-03570-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 08/04/2022] [Indexed: 12/13/2022] Open
Abstract
With the advent of an aging society, the incidence of dementia is increasing, resulting in a vast burden on society. It is increasingly acknowledged that neuroinflammation is implicated in various neurological diseases with cognitive dysfunction such as Alzheimer’s disease, multiple sclerosis, ischemic stroke, traumatic brain injury, and central nervous system infections. As an important neuroinflammatory factor, interleukin-33 (IL-33) is highly expressed in various tissues and cells in the mammalian brain, where it plays a role in the pathogenesis of a number of central nervous system conditions. Reams of previous studies have shown that IL-33 has both pro- and anti-inflammatory effects, playing dual roles in the progression of diseases linked to cognitive impairment by regulating the activation and polarization of immune cells, apoptosis, and synaptic plasticity. This article will summarize the current findings on the effects IL-33 exerts on cognitive function by regulating neuroinflammation, and attempt to explore possible therapeutic strategies for cognitive disorders based on the adverse and protective mechanisms of IL-33.
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Affiliation(s)
- Xiuqin Rao
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Fuzhou Hua
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Lieliang Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Yue Lin
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Pu Fang
- Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Shoulin Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Jun Ying
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Xifeng Wang
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
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17
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Jayarathne HSM, Debarba LK, Jaboro JJ, Ginsburg BC, Miller RA, Sadagurski M. Neuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM-HET3 mice. Aging Cell 2022; 21:e13653. [PMID: 35707855 PMCID: PMC9282842 DOI: 10.1111/acel.13653] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/13/2022] [Accepted: 05/25/2022] [Indexed: 01/24/2023] Open
Abstract
The aging brain is characterized by progressive increases in neuroinflammation and central insulin resistance, which contribute to neurodegenerative diseases and cognitive impairment. Recently, the Interventions Testing Program demonstrated that the anti-diabetes drug, Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor, led to lower fasting glucose and improved glucose tolerance in both sexes, but extended median lifespan by 14% in male mice only. Here, we show that Cana treatment significantly improved central insulin sensitivity in the hypothalamus and the hippocampus of 30-month-old male mice. Aged males produce more robust neuroimmune responses than aged females. Remarkably, Cana-treated male and female mice showed significant reductions in age-associated hypothalamic gliosis with a decrease in inflammatory cytokine production by microglia. However, in the hippocampus, Cana reduced microgliosis and astrogliosis in males, but not in female mice. The decrease in microgliosis was partially correlated with reduced phosphorylation of S6 kinase in microglia of Cana-treated aged male, but not female mice. Thus, Cana treatment improved insulin responsiveness in aged male mice. Furthermore, Cana treatment improved exploratory and locomotor activity of 30-month-old male but not female mice. Taken together, we demonstrate the sex-specific neuroprotective effects of Cana treatment, suggesting its application for the potential treatment of neurodegenerative diseases.
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Affiliation(s)
- Hashan S. M. Jayarathne
- Department of Biological Sciences, IBio (Integrative Biosciences Center)Wayne State UniversityDetroitMichiganUSA
| | - Lucas K. Debarba
- Department of Biological Sciences, IBio (Integrative Biosciences Center)Wayne State UniversityDetroitMichiganUSA
| | - Jacob J. Jaboro
- Department of Biological Sciences, IBio (Integrative Biosciences Center)Wayne State UniversityDetroitMichiganUSA
| | - Brett C. Ginsburg
- Department of Psychiatry and Behavioral SciencesUniversity of Texas Health Science CenterSan AntonioTexasUSA
| | - Richard A. Miller
- Department of Pathology and Geriatrics CenterUniversity of MichiganAnn ArborMichiganUSA
| | - Marianna Sadagurski
- Department of Biological Sciences, IBio (Integrative Biosciences Center)Wayne State UniversityDetroitMichiganUSA
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18
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Connolly MG, Bruce SR, Kohman RA. Exercise duration differentially effects age-related neuroinflammation and hippocampal neurogenesis. Neuroscience 2022; 490:275-286. [PMID: 35331843 PMCID: PMC9038708 DOI: 10.1016/j.neuroscience.2022.03.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 03/10/2022] [Accepted: 03/16/2022] [Indexed: 12/14/2022]
Abstract
The physiological effects of exercise vary as a function of frequency and length. However, research on the duration-dependent effects of exercise has focused primarily on young adults and less is known about the influence of exercise duration in the aged. The current study compared the effects of short-term and long-term running wheel access on hippocampal neurogenesis and neuroimmune markers in aged (19-23 months) male C57BL/6J mice. Aged mice were given 24-hour access to a running wheel for 14 days (short-term) or 51 days (long-term). Groups of non-running aged and young (5 months) mice served as comparison groups to detect age-related differences and effects of exercise. Long-term, but not short-term, exercise increased hippocampal neurogenesis as assessed by number of doublecortin (DCX) positive cells in the granular cell layer. Assessment of cytokines, receptors, and glial-activation markers showed the expected age-related increase compared to young controls. In the aged, exercise as a function of duration regulated select aspects of the neuroimmune profile. For instance, hippocampal expression of interleukin (IL)-10 was increased only following long-term exercise. While in contrast brain levels of IL-6 were reduced by both short- and long-term exercise. Additional findings showed that exercise does not modulate all aspects of age-related neuroinflammation and/or may have differential effects in hippocampal compared to brain samples. Overall, the data indicate that increasing exercise duration produces more robust effects on immune modulation and hippocampal neurogenesis.
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Affiliation(s)
- Meghan G Connolly
- University of Illinois Urbana-Champaign, Department of Animal Sciences, Champaign, IL, USA.
| | - Spencer R Bruce
- University of North Carolina Wilmington, Department of Psychology, Wilmington, NC, USA.
| | - Rachel A Kohman
- University of North Carolina Wilmington, Department of Psychology, Wilmington, NC, USA.
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19
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Clare AJ, Liu J, Copland DA, Theodoropoulou S, Dick AD. Unravelling the therapeutic potential of IL-33 for atrophic AMD. Eye (Lond) 2022; 36:266-272. [PMID: 34531552 PMCID: PMC8807696 DOI: 10.1038/s41433-021-01725-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/08/2021] [Accepted: 07/27/2021] [Indexed: 02/08/2023] Open
Abstract
Age-related macular degeneration (AMD), a degenerative disease affecting the retinal pigment epithelium (RPE) and photoreceptors in the macula, is the leading cause of central blindness in the elderly. AMD progresses to advanced stages of the disease, atrophic AMD (aAMD), or in 15% of cases "wet" or neovascular AMD (nAMD), associated with substantial vision loss. Whilst there has been advancement in therapies treating nAMD, to date, there are no licenced effective treatments for the 85% affected by aAMD, with disease managed by changes to diet, vitamin supplements, and regular monitoring. AMD has a complex pathogenesis, involving highly integrated and common age-related disease pathways, including dysregulated complement/inflammation, impaired autophagy, and oxidative stress. The intricacy of AMD pathogenesis makes therapeutic development challenging and identifying a target that combats the converging disease pathways is essential to provide a globally effective treatment. Interleukin-33 is a cytokine, classically known for the proinflammatory role it plays in allergic disease. Recent evidence across degenerative and inflammatory disease conditions reveals a diverse immune-modulatory role for IL-33, with promising therapeutic potential. Here, we will review IL-33 function in disease and discuss the future potential for this homeostatic cytokine in treating AMD.
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Affiliation(s)
- Alison J. Clare
- grid.5337.20000 0004 1936 7603Academic Unit of Ophthalmology, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Jian Liu
- grid.5337.20000 0004 1936 7603Academic Unit of Ophthalmology, Translational Health Sciences, University of Bristol, Bristol, UK
| | - David A. Copland
- grid.5337.20000 0004 1936 7603Academic Unit of Ophthalmology, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Sofia Theodoropoulou
- grid.5337.20000 0004 1936 7603Academic Unit of Ophthalmology, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Andrew D. Dick
- grid.5337.20000 0004 1936 7603Academic Unit of Ophthalmology, Translational Health Sciences, University of Bristol, Bristol, UK ,grid.5337.20000 0004 1936 7603School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK ,grid.439257.e0000 0000 8726 5837NIHR Biomedical Research Centre of Ophthalmology, Moorfields Eye Hospital, London, UK ,grid.83440.3b0000000121901201UCL Institute of Ophthalmology, London, UK
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20
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Role of IL-33/ST2 Axis in Chronic Inflammatory Neurological Disorderss. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2021. [DOI: 10.2478/sjecr-2020-0038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
Interleukin-33 (IL-33) is a member of IL-1 family of cytokines, produced constitutively by fibroblasts, endothelial cells, and epithelial cells. IL-33 can be released passively from cells during tissue damage and cell necrosis, suggesting that it may act as an alarmin. Function of IL-33 is mediated by its interaction with ST2 molecule that is expressed on many immune cells: Th2 lymphocytes, NK, NKT and mast cells, monocytes, dendritic cells and granulocytes. IL-33/ST2 pathway plays, often dual, roles in different physiological and inflammatory processes, mediating both, pathological immune responses and tissue repair. Expression of IL-33 in the central nervous system (CNS) is significantly enhanced during various pathological processes, indicating its important role in the pathogenesis of neurological inflammatory and degenerative diseases. In this review the biological features, expression of IL-33 and its ligand ST2 in CNS, and the role of IL- 33/ST2 pathway in development of Alzheimer’s disease and multiple sclerosis are discussed.
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21
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Borovcanin MM, Vesic K. Breast cancer in schizophrenia could be interleukin-33-mediated. World J Psychiatry 2021; 11:1065-1074. [PMID: 34888174 PMCID: PMC8613763 DOI: 10.5498/wjp.v11.i11.1065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/21/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Recent epidemiological and genetic studies have revealed an interconnection between schizophrenia and breast cancer. The mutual underlying pathophysiological mechanisms may be immunologically driven. A new cluster of molecules called alarmins may be involved in sterile brain inflammation, and we have already reported the potential impact of interleukin-33 (IL-33) on positive symptoms onset and the role of its soluble trans-membranes full length receptor (sST2) on amelioration of negative symptoms in schizophrenia genesis. Furthermore, these molecules have already been shown to be involved in breast cancer etiopathogenesis. In this review article, we aim to describe the IL-33/suppressor of tumorigenicity 2 (ST2) axis as a crossroad in schizophrenia-breast cancer comorbidity. Considering that raloxifene could be tissue-specific and improve cognition and that tamoxifen resistance in breast carcinoma could be improved by strategies targeting IL-33, these selective estrogen receptor modulators could be useful in complementary treatment. These observations could guide further somatic, as well as psychiatric therapeutical protocols by incorporating what is known about immunity in schizophrenia.
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Affiliation(s)
- Milica M Borovcanin
- Department of Psychiatry, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Serbia
| | - Katarina Vesic
- Department of Neurology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Serbia
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22
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Chung YH, Qian Q, Huang HY, Chiu WT, Yang CS, Tzeng SF. The Nuclear Function of IL-33 in Desensitization to DNA Damaging Agent and Change of Glioma Nuclear Structure. Front Cell Neurosci 2021; 15:713336. [PMID: 34744630 PMCID: PMC8565524 DOI: 10.3389/fncel.2021.713336] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 09/16/2021] [Indexed: 11/23/2022] Open
Abstract
Glioma, the most common subtype of primary brain tumor, is an aggressive and highly invasive neurologically tumor among human cancers. Interleukin-33 (IL-33) is considered as a dual functional cytokine, an alarmin upon tissue damage and a nuclear chromatin-associated protein. Despite that, IL-33 is known to foster the formation of the inflammatory tumor microenvironment and facilitate glioma progression, evidence showing nuclear IL-33 function is still poor. In this study using lentivirus-mediated IL-33 gene knockdown (IL33KD) and IL-33 overexpression (IL33oe) in rat C6 glioma cells and human glioma cell lines (U251MG and U87MG), we found that IL33oe-glioma cells had resistance to the insults of the alkylating agent, temozolomide (TMZ), possibly because of the increased expression of DNA repair genes (i.e., BRCA1, BRCA2, Rad51, FANCB, and FANCD) in IL33oe-glioma cells. Alternatively, examination of glioma nuclear shape from transmission electron microscopy (TEM) imaging analysis and immunofluorescence for histone protein H2A staining showed that IL33KD attenuated the abnormal cancerous nuclear characteristic, such as indentation, long clefts, and multiple nucleoids. Yet, IL33oe promoted the changes in glioma nuclear shapes, such as the formation of multiple lobes. We further found that histone proteins, H2A and H3, were reduced in IL33KD glioma cells. The non-histone DNA-binding nucleoproteins, the high mobility group A1 (HMGA1) and HMGA2, were also downregulated by IL33KD. In contrast, IL33oe increased H2A and H3 proteins and HMGA1 and HMGA2 in glioma cells. Altogether, the upregulation of nuclear IL-33 expression was along with an increase in the expression of DNA repair genes, contributing to the desensitization of glioma cells to DNA damaging agents. Moreover, nuclear IL-33 proteins in cooperation with chromatin-associated proteins regulate glioma nuclear structure, which might be crucial for glioma progression and malignancy.
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Affiliation(s)
- Yu-Han Chung
- Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Qiu Qian
- Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Hsin-Ying Huang
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan
| | - Wen-Tai Chiu
- Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Shi Yang
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan
| | - Shun-Fen Tzeng
- Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
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23
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Yeung SSH, Ho YS, Chang RCC. The role of meningeal populations of type II innate lymphoid cells in modulating neuroinflammation in neurodegenerative diseases. Exp Mol Med 2021; 53:1251-1267. [PMID: 34489558 PMCID: PMC8492689 DOI: 10.1038/s12276-021-00660-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/28/2021] [Accepted: 06/30/2021] [Indexed: 02/08/2023] Open
Abstract
Recent research into meningeal lymphatics has revealed a never-before appreciated role of type II innate lymphoid cells (ILC2s) in modulating neuroinflammation in the central nervous system (CNS). To date, the role of ILC2-mediated inflammation in the periphery has been well studied. However, the exact distribution of ILC2s in the CNS and therefore their putative role in modulating neuroinflammation in neurodegenerative diseases such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and major depressive disorder (MDD) remain highly elusive. Here, we review the current evidence of ILC2-mediated modulation of neuroinflammatory cues (i.e., IL-33, IL-25, IL-5, IL-13, IL-10, TNFα, and CXCL16-CXCR6) within the CNS, highlight the distribution of ILC2s in both the periphery and CNS, and discuss some challenges associated with cell type-specific targeting that are important for therapeutics. A comprehensive understanding of the roles of ILC2s in mediating and responding to inflammatory cues may provide valuable insight into potential therapeutic strategies for many dementia-related disorders.
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Affiliation(s)
- Sherry Sin-Hang Yeung
- grid.194645.b0000000121742757Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China
| | - Yuen-Shan Ho
- grid.16890.360000 0004 1764 6123School of Nursing, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR China
| | - Raymond Chuen-Chung Chang
- grid.194645.b0000000121742757Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China ,grid.194645.b0000000121742757State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR China
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24
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Sun Y, Wen Y, Wang L, Wen L, You W, Wei S, Mao L, Wang H, Chen Z, Yang X. Therapeutic Opportunities of Interleukin-33 in the Central Nervous System. Front Immunol 2021; 12:654626. [PMID: 34079543 PMCID: PMC8165230 DOI: 10.3389/fimmu.2021.654626] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 05/04/2021] [Indexed: 01/14/2023] Open
Abstract
Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is involved in various diseases. IL-33 exerts its effects via its heterodimeric receptor complex, which comprises suppression of tumorigenicity 2 (ST2) and the IL-1 receptor accessory protein (IL-1RAP). Increasing evidence has demonstrated that IL-33/ST2 signaling plays diverse but crucial roles in the homeostasis of the central nervous system (CNS) and the pathogenesis of CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, infection, trauma, and ischemic stroke. In the current review, we focus on the functional roles and cellular signaling mechanisms of IL-33 in the CNS and evaluate the potential for diagnostic and therapeutic applications.
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Affiliation(s)
- Yun Sun
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Yankai Wen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Luxi Wang
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang Wen
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Wendong You
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Shuang Wei
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Lin Mao
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Hao Wang
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Zuobing Chen
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Xiaofeng Yang
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
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25
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Lau SF, Fu AKY, Ip NY. Cytokine signaling convergence regulates the microglial state transition in Alzheimer's disease. Cell Mol Life Sci 2021; 78:4703-4712. [PMID: 33847763 PMCID: PMC8195901 DOI: 10.1007/s00018-021-03810-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 03/01/2021] [Accepted: 03/05/2021] [Indexed: 12/13/2022]
Abstract
Genetic analyses have revealed the pivotal contribution of microglial dysfunctions to the pathogenesis of Alzheimer's disease (AD). Along AD progression, the accumulation of danger-associated molecular patterns (DAMPs) including beta-amyloid and hyperphosphorylated tau continuously stimulates microglia, which results in their chronic activation. Chronically activated microglia secrete excessive pro-inflammatory cytokines, which further regulate microglial responses towards DAMPs. This has spurred longstanding interest in targeting cytokine-induced microglial responses for AD therapeutic development. However, the cytokine-induced microglial state transition is not comprehensively understood. Cytokines are assumed to induce microglial state transition from a resting state to an activated state. However, recent evidence indicate that this microglial state transition involves multiple sequential functional states. Moreover, the mechanisms by which different functional states within the cytokine-induced microglial state transition regulate AD pathology remain unclear. In this review, we summarize how different cytokine signaling pathways, including those of IL-33 (interleukin-33), NLRP3 inflammasome-IL-1β, IL-10, and IL-12/IL-23, regulate microglial functions in AD. Furthermore, we discuss how the modulation of these cytokine signaling pathways can result in beneficial outcomes in AD. Finally, we describe a stepwise functional state transition of microglia induced by cytokine signaling that can provide insights into the molecular basis of the beneficial effects of cytokine modulation in AD and potentially aid therapeutic development.
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Affiliation(s)
- Shun-Fat Lau
- Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
- Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
| | - Amy K Y Fu
- Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
- Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
- Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, 518057, Guangdong, China
| | - Nancy Y Ip
- Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
- Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
- Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, 518057, Guangdong, China.
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26
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Requirement of brain interleukin33 for aquaporin4 expression in astrocytes and glymphatic drainage of abnormal tau. Mol Psychiatry 2021; 26:5912-5924. [PMID: 33432186 PMCID: PMC8273186 DOI: 10.1038/s41380-020-00992-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 11/17/2020] [Accepted: 12/07/2020] [Indexed: 02/07/2023]
Abstract
Defective aquaporin4 (AQP4)-mediated glymphatic drainage has been linked to tauopathy and amyloid plaque in Alzheimer's disease. We now show that brain interleukin33 (IL33) is required for regulation of AQP4 expression in astrocytes, especially those at neuron-facing membrane domain (n-AQP4). First, IL33-deficient (Il33-/-) mice showed a loss of n-AQP4 after middle age, which coincided with a rapid accumulation of abnormal tau in neurons and a reduction in drainage of abnormal tau to peripheral tissues. Second, injection of recombinant IL33 induced robust expression of AQP4 at perivascular endfoot (p-AQP4) of astrocytes, but not n-AQP4, in Il33-/- brains. Although the increased p-AQP4 greatly accelerated drainage of intracerebroventricularly injected peptides, it did not substantially accelerate drainage of abnormal tau. These results suggest that p-AQP4 drives overall convective flow toward perivenous space, i.e., glymphatics, whereas n-AQP4 may generate an aqueous flow away from neurons to remove neuronal wastes, e.g., abnormal tau. We have previously shown the role of brain IL33 in DNA repair and autophagy in neurons with oxidative stress. Now, we show that IL33 deficiency also impairs glymphatic drainage. Defects in those mechanisms together may lead to chronic neurodegeneration and tauopathy at old age in IL33-deficient mice.
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27
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Femminella GD, Harold D, Scott J, Williams J, Edison P. The Differential Influence of Immune, Endocytotic, and Lipid Metabolism Genes on Amyloid Deposition and Neurodegeneration in Subjects at Risk of Alzheimer's Disease. J Alzheimers Dis 2020; 79:127-139. [PMID: 33216025 DOI: 10.3233/jad-200578] [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: 11/15/2022]
Abstract
BACKGROUND Over 20 single-nucleotide polymorphisms (SNPs) are associated with increased risk of Alzheimer's disease (AD). We categorized these loci into immunity, lipid metabolism, and endocytosis pathways, and associated the polygenic risk scores (PRS) calculated, with AD biomarkers in mild cognitive impairment (MCI) subjects. OBJECTIVE The aim of this study was to identify associations between pathway-specific PRS and AD biomarkers in patients with MCI and healthy controls. METHODS AD biomarkers ([18F]Florbetapir-PET SUVR, FDG-PET SUVR, hippocampal volume, CSF tau and amyloid-β levels) and neurocognitive tests scores were obtained in 258 healthy controls and 451 MCI subjects from the ADNI dataset at baseline and at 24-month follow up. Pathway-related (immunity, lipid metabolism, and endocytosis) and total polygenic risk scores were calculated from 20 SNPs. Multiple linear regression analysis was used to test predictive value of the polygenic risk scores over longitudinal biomarker and cognitive changes. RESULTS Higher immune risk score was associated with worse cognitive measures and reduced glucose metabolism. Higher lipid risk score was associated with increased amyloid deposition and cortical hypometabolism. Total, immune, and lipid scores were associated with significant changes in cognitive measures, amyloid deposition, and brain metabolism. CONCLUSION Polygenic risk scores highlights the influence of specific genes on amyloid-dependent and independent pathways; and these pathways could be differentially influenced by lipid and immune scores respectively.
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Affiliation(s)
| | | | - James Scott
- Imperial College London, London, United Kingdom
| | - Julie Williams
- School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Paul Edison
- Imperial College London, London, United Kingdom
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28
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Still KM, Batista SJ, O’Brien CA, Oyesola OO, Früh SP, Webb LM, Smirnov I, Kovacs MA, Cowan MN, Hayes NW, Thompson JA, Tait Wojno ED, Harris TH. Astrocytes promote a protective immune response to brain Toxoplasma gondii infection via IL-33-ST2 signaling. PLoS Pathog 2020; 16:e1009027. [PMID: 33108405 PMCID: PMC7647122 DOI: 10.1371/journal.ppat.1009027] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 11/06/2020] [Accepted: 09/29/2020] [Indexed: 12/27/2022] Open
Abstract
It is of great interest to understand how invading pathogens are sensed within the brain, a tissue with unique challenges to mounting an immune response. The eukaryotic parasite Toxoplasma gondii colonizes the brain of its hosts, and initiates robust immune cell recruitment, but little is known about pattern recognition of T. gondii within brain tissue. The host damage signal IL-33 is one protein that has been implicated in control of chronic T. gondii infection, but, like many other pattern recognition pathways, IL-33 can signal peripherally, and the specific impact of IL-33 signaling within the brain is unclear. Here, we show that IL-33 is expressed by oligodendrocytes and astrocytes during T. gondii infection, is released locally into the cerebrospinal fluid of T. gondii-infected animals, and is required for control of infection. IL-33 signaling promotes chemokine expression within brain tissue and is required for the recruitment and/or maintenance of blood-derived anti-parasitic immune cells, including proliferating, IFN-γ-expressing T cells and iNOS-expressing monocytes. Importantly, we find that the beneficial effects of IL-33 during chronic infection are not a result of signaling on infiltrating immune cells, but rather on radio-resistant responders, and specifically, astrocytes. Mice with IL-33 receptor-deficient astrocytes fail to mount an adequate adaptive immune response in the CNS to control parasite burden-demonstrating, genetically, that astrocytes can directly respond to IL-33 in vivo. Together, these results indicate a brain-specific mechanism by which IL-33 is released locally, and sensed locally, to engage the peripheral immune system in controlling a pathogen.
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Affiliation(s)
- Katherine M. Still
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia, United States of America
| | - Samantha J. Batista
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia, United States of America
| | - Carleigh A. O’Brien
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia, United States of America
| | - Oyebola O. Oyesola
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University, Ithaca, New York, United States of America
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
| | - Simon P. Früh
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University, Ithaca, New York, United States of America
| | - Lauren M. Webb
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
| | - Igor Smirnov
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia, United States of America
| | - Michael A. Kovacs
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia, United States of America
| | - Maureen N. Cowan
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia, United States of America
| | - Nikolas W. Hayes
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia, United States of America
| | - Jeremy A. Thompson
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia, United States of America
| | - Elia D. Tait Wojno
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
| | - Tajie H. Harris
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia, United States of America
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Roda AR, Montoliu-Gaya L, Serra-Mir G, Villegas S. Both Amyloid-β Peptide and Tau Protein Are Affected by an Anti-Amyloid-β Antibody Fragment in Elderly 3xTg-AD Mice. Int J Mol Sci 2020; 21:E6630. [PMID: 32927795 PMCID: PMC7554787 DOI: 10.3390/ijms21186630] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 12/15/2022] Open
Abstract
Alzheimer's disease (AD) is the most common dementia worldwide. According to the amyloid hypothesis, the early accumulation of the Aβ-peptide triggers tau phosphorylation, synaptic dysfunction, and eventually neuronal death leading to cognitive impairment, as well as behavioral and psychological symptoms of dementia. ScFv-h3D6 is a single-chain variable fragment that has already shown its ability to diminish the amyloid burden in 5-month-old 3xTg-AD mice. However, tau pathology is not evident at this early stage of the disease in this mouse model. In this study, the effects of scFv-h3D6 on Aβ and tau pathologies have been assessed in 22-month-old 3xTg-AD mice. Briefly, 3xTg-AD female mice were treated for 2 weeks with scFv-h3D6 and compared with 3xTg-AD and non-transgenic (NTg) mice treated with PBS. The treatment with scFv-h3D6 was unequivocally effective in reducing the area of Aβ staining. Furthermore, a tendency for a reduction in tau levels was also observed after treatment that points to the interplay between Aβ and tau pathologies. The pro-inflammatory state observed in the 3xTg-AD mice did not progress after scFv-h3D6 treatment. In addition, the treatment did not alter the levels of apolipoprotein E or apolipoprotein J. Thus, a 2-week treatment with scFv-h3D6 was able to reduce AD-like pathology in elderly 3xTg-AD female mice.
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Affiliation(s)
- Alejandro R. Roda
- Protein Design and Immunotherapy Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (A.R.R.); (L.M.-G.); (G.S.-M.)
| | - Laia Montoliu-Gaya
- Protein Design and Immunotherapy Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (A.R.R.); (L.M.-G.); (G.S.-M.)
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 41 Mölndal, Sweden
| | - Gabriel Serra-Mir
- Protein Design and Immunotherapy Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (A.R.R.); (L.M.-G.); (G.S.-M.)
| | - Sandra Villegas
- Protein Design and Immunotherapy Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (A.R.R.); (L.M.-G.); (G.S.-M.)
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30
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Abstract
PURPOSE OF REVIEW Over the last year, research into the immunological and inflammatory signatures of frontotemporal lobar degeneration (FTLD) has accelerated greatly. Herein, we highlight recently proposed roles of brain-resident microglia as well as peripheral myeloid cells in frontotemporal dementia (FTD)-spectrum disorders. RECENT FINDINGS Recent unbiased genetic, transcriptomic, and proteomic surveys using human data confirm significantly altered immune-function genes as well as transcript and protein modules associated with inflammatory and immune function. Beyond human studies, novel animal models indicate important roles for both microglia and monocytes, and central involvement of genes such as Trem2, Apoe, and Tbk1. SUMMARY The importance of neuroinflammatory activity in FTD pathophysiology is unambiguous, but whether this activity is primarily beneficial or detrimental remains unclear, with variable results reported for distinct disease paradigms. Going forward, it will be crucial to determine which types of microglial and peripheral myeloid responses are favorable, in response to which specific proteinopathies, and at which point in disease course.
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31
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Sung HY, Chen WY, Huang HT, Wang CY, Chang SB, Tzeng SF. Down-regulation of interleukin-33 expression in oligodendrocyte precursor cells impairs oligodendrocyte lineage progression. J Neurochem 2019; 150:691-708. [PMID: 31165473 DOI: 10.1111/jnc.14788] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 04/15/2019] [Accepted: 05/26/2019] [Indexed: 12/24/2022]
Abstract
Interleukin-33 (IL-33), a member of the IL1 family, has been found to be expressed in oligodendrocytes (OLGs) and released as an alarmin from injured OLGs to work on other glial cell-types in the central nervous system. However, its functional role in OLGs remains unclear. Herein, we present that IL-33 was mainly expressed in the nucleus of CC1+ -oligodendrocytes (OLGs) in mouse and rat corpus callosum, as well as NG2+ -oligodendrocyte precursor cells (OPCs). The in vitro study indicated that the amount of IL-33 expressing in OPCs was higher when compared to that detected in OLGs. Results from the experiments using lentivirus-mediated shRNA delivery against IL-33 expression (IL33-KD) in OPCs showed that IL33-KD reduced the differentiation of OLGs into mature OLGs along with the down-regulation of OLG differentiation-related genes and mature OLG marker proteins, myelin basic protein (MBP) and proteolipid protein (PLP). Alternatively, we observed reduced differentiation of OLGs that were prepared from the brains of IL-33 gene knockout (IL33-KO) mice with anxiolytic-like behavior. Observations were correlated with the results showing lower levels of MBP and PLP in IL33-KO cultures than those detected in the control cultures prepared from wildtype (WT) mice. Transmission Electron Microscopy (TEM) analysis revealed that the myelin structures in the corpus callosum of the IL33-KO mice were impaired compared to those observed in the WT mice. Overall, this study provides important evidence that declined expression of IL-33 in OPCs suppresses the maturation of OLGs. Moreover, gene deficiency of IL-33 can disrupt OLG maturation and interfere with myelin compaction. Cover Image for this issue: doi: 10.1111/jnc.14522.
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Affiliation(s)
- Hsin-Yu Sung
- Department of Life Sciences, College of Biological Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Yu Chen
- Institute for Translational Research in Biomedicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Hui-Ting Huang
- Department of Life Sciences, College of Biological Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Yen Wang
- Department of Life Sciences, College of Biological Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Song-Bin Chang
- Department of Life Sciences, College of Biological Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Shun-Fen Tzeng
- Department of Life Sciences, College of Biological Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan
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Dionisio-Santos DA, Olschowka JA, O'Banion MK. Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer's disease. J Neuroinflammation 2019; 16:74. [PMID: 30953557 PMCID: PMC6449993 DOI: 10.1186/s12974-019-1453-0] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 03/18/2019] [Indexed: 12/21/2022] Open
Abstract
Neuroinflammation is considered one of the cardinal features of Alzheimer’s disease (AD). Neuritic plaques composed of amyloid β and neurofibrillary tangle-laden neurons are surrounded by reactive astrocytes and microglia. Exposure of microglia, the resident myeloid cell of the CNS, to amyloid β causes these cells to acquire an inflammatory phenotype. While these reactive microglia are important to contain and phagocytose amyloid plaques, their activated phenotype impacts CNS homeostasis. In rodent models, increased neuroinflammation promoted by overexpression of proinflammatory cytokines can cause an increase in hyperphosphorylated tau and a decrease in hippocampal function. The peripheral immune system can also play a detrimental or beneficial role in CNS inflammation. Systemic inflammation can increase the risk of developing AD dementia, and chemokines released directly by microglia or indirectly by endothelial cells can attract monocytes and T lymphocytes to the CNS. These peripheral immune cells can aid in amyloid β clearance or modulate microglia responses, depending on the cell type. As such, several groups have targeted the peripheral immune system to modulate chronic neuroinflammation. In this review, we focus on the interplay of immunomodulating factors and cell types that are being investigated as possible therapeutic targets for the treatment or prevention of AD.
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Affiliation(s)
- Dawling A Dionisio-Santos
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 603, Rochester, NY, 14642, USA
| | - John A Olschowka
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 603, Rochester, NY, 14642, USA
| | - M Kerry O'Banion
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 603, Rochester, NY, 14642, USA.
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33
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Garbern JC, Williams J, Kristl AC, Malick A, Rachmin I, Gaeta B, Ahmed N, Vujic A, Libby P, Lee RT. Dysregulation of IL-33/ST2 signaling and myocardial periarteriolar fibrosis. J Mol Cell Cardiol 2019; 128:179-186. [PMID: 30763587 PMCID: PMC6402609 DOI: 10.1016/j.yjmcc.2019.01.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/31/2018] [Accepted: 01/22/2019] [Indexed: 02/07/2023]
Abstract
Microvascular dysfunction in the heart and its association with periarteriolar fibrosis may contribute to the diastolic dysfunction seen in heart failure with preserved ejection fraction. Interleukin-33 (IL-33) prevents global myocardial fibrosis in a pressure overloaded left ventricle by acting via its receptor, ST2 (encoded by the gene, Il1rl1); however, whether this cytokine can also modulate periarteriolar fibrosis remains unclear. We utilized two approaches to explore the role of IL-33/ST2 in periarteriolar fibrosis. First, we studied young and old wild type mice to test the hypothesis that IL-33 and ST2 expression change with age. Second, we produced pressure overload in mice deficient in IL-33 or ST2 by transverse aortic constriction (TAC). With age, IL-33 expression increased and ST2 expression decreased. These alterations accompanied increased periarteriolar fibrosis in aged mice. Mice deficient in ST2 but not IL-33 had a significant increase in periarteriolar fibrosis following TAC compared to wild type mice. Thus, loss of ST2 signaling rather than changes in IL-33 expression may contribute to periarteriolar fibrosis during aging or pressure overload, but manipulating this pathway alone may not prevent or reverse fibrosis.
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Affiliation(s)
- Jessica C Garbern
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, United States of America; Department of Cardiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, United States of America
| | - Jason Williams
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, United States of America
| | - Amy C Kristl
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, United States of America
| | - Alyyah Malick
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, United States of America
| | - Inbal Rachmin
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, United States of America
| | - Benjamin Gaeta
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, United States of America
| | - Nafis Ahmed
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, United States of America
| | - Ana Vujic
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, United States of America
| | - Peter Libby
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, United States of America.
| | - Richard T Lee
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, United States of America; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, United States of America.
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34
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Fairlie-Clarke K, Barbour M, Wilson C, Hridi SU, Allan D, Jiang HR. Expression and Function of IL-33/ST2 Axis in the Central Nervous System Under Normal and Diseased Conditions. Front Immunol 2018; 9:2596. [PMID: 30515150 PMCID: PMC6255965 DOI: 10.3389/fimmu.2018.02596] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 10/22/2018] [Indexed: 12/11/2022] Open
Abstract
Interleukin-33 (IL-33) is a well-recognized immunomodulatory cytokine which plays critical roles in tissue function and immune-mediated diseases. The abundant expression of IL-33 in brain and spinal cord prompted many scientists to explore its unique role in the central nervous system (CNS) under physiological and pathological conditions. Indeed emerging evidence from over a decade's research suggests that IL-33 acts as one of the key molecular signaling cues coordinating the network between the immune and CNS systems, particularly during the development of neurological diseases. Here, we highlight the recent advances in our knowledge regarding the distribution and cellular localization of IL-33 and its receptor ST2 in specific CNS regions, and more importantly the key roles IL-33/ST2 signaling pathway play in CNS function under normal and diseased conditions.
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Affiliation(s)
| | | | | | | | | | - Hui-Rong Jiang
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
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