1
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Perochon T, Krsnik Z, Massimo M, Ruchiy Y, Romero AL, Mohammadi E, Li X, Long KR, Parkkinen L, Blomgren K, Lagache T, Menassa DA, Holcman D. Unraveling microglial spatial organization in the developing human brain with DeepCellMap, a deep learning approach coupled with spatial statistics. Nat Commun 2025; 16:1577. [PMID: 39948387 PMCID: PMC11825940 DOI: 10.1038/s41467-025-56560-z] [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: 02/26/2024] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
Mapping cellular organization in the developing brain presents significant challenges due to the multidimensional nature of the data, characterized by complex spatial patterns that are difficult to interpret without high-throughput tools. Here, we present DeepCellMap, a deep-learning-assisted tool that integrates multi-scale image processing with advanced spatial and clustering statistics. This pipeline is designed to map microglial organization during normal and pathological brain development and has the potential to be adapted to any cell type. Using DeepCellMap, we capture the morphological diversity of microglia, identify strong coupling between proliferative and phagocytic phenotypes, and show that distinct spatial clusters rarely overlap as human brain development progresses. Additionally, we uncover an association between microglia and blood vessels in fetal brains exposed to maternal SARS-CoV-2. These findings offer insights into whether various microglial phenotypes form networks in the developing brain to occupy space, and in conditions involving haemorrhages, whether microglia respond to, or influence changes in blood vessel integrity. DeepCellMap is available as an open-source software and is a powerful tool for extracting spatial statistics and analyzing cellular organization in large tissue sections, accommodating various imaging modalities. This platform opens new avenues for studying brain development and related pathologies.
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Affiliation(s)
- Theo Perochon
- Group of Data Modeling and Computational Biology, IBENS, École Normale Supérieure, Paris, France
| | - Zeljka Krsnik
- Croatian Institute for Brain Research, University of Zagreb, Zagreb, Croatia
| | - Marco Massimo
- Centre for Developmental Neurobiology, MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK
| | - Yana Ruchiy
- Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
| | | | - Elyas Mohammadi
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden
| | - Xiaofei Li
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden
| | - Katherine R Long
- Centre for Developmental Neurobiology, MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK
| | - Laura Parkkinen
- Department of Neuropathology and The Queen's College, University of Oxford, Oxford, United Kingdom
| | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
| | - Thibault Lagache
- BioImage Analysis Unit, CNRS UMR3691, Institut Pasteur, Université Paris Cité, Paris, France.
| | - David A Menassa
- Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
- Department of Neuropathology and The Queen's College, University of Oxford, Oxford, United Kingdom.
| | - David Holcman
- Group of Data Modeling and Computational Biology, IBENS, École Normale Supérieure, Paris, France.
- DAMPT, University of Cambridge, DAMPT and Churchill College, Cambridge, United Kingdom.
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2
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Le LHD, Eliseeva S, Plunk E, Kara-Pabani K, Li H, Yarovinsky F, Majewska AK. The microglial response to inhibition of Colony-stimulating-factor-1 receptor by PLX3397 differs by sex in adult mice. Cell Rep 2025; 44:115176. [PMID: 39842435 DOI: 10.1016/j.celrep.2024.115176] [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: 04/08/2024] [Revised: 10/08/2024] [Accepted: 12/18/2024] [Indexed: 01/24/2025] Open
Abstract
Microglia, the resident macrophages of the brain, are derived from the yolk sac and colonize the brain before the blood-brain barrier forms. Once established, they expand locally and require Colony-stimulating-factor-1 receptor (CSF1R) signaling for their development and maintenance. CSF1R inhibitors have been used extensively to deplete microglia in the healthy and diseased brain. In this study, we demonstrated sex-dependent differences in the microglial response to the CSF1R inhibitor PLX3397. Male mice exhibited greater microglial depletion compared to females. Transcriptomic and flow cytometry analysis revealed sex-specific differences in the remaining microglia population, with female microglia upregulating autophagy and proteostasis pathways while male microglia increased mitobiogenesis. Furthermore, manipulating key microglial receptors by using different transgenic mouse lines resulted in changes in depletion efficacies that were also sex dependent. These findings suggest sex-dependent microglial survival mechanisms, which might contribute to the well-documented sex differences in various neurological disorders.
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Affiliation(s)
- Linh H D Le
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY 14642, USA
| | - Sophia Eliseeva
- Department of Microbiology and Immunology, Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA
| | - Elizabeth Plunk
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY 14642, USA; Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA
| | - Kallam Kara-Pabani
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY 14642, USA
| | - Herman Li
- Medical Scientist Training Program, University of Rochester, Rochester, NY 14642, USA
| | - Felix Yarovinsky
- Department of Microbiology and Immunology, Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA
| | - Ania K Majewska
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY 14642, USA; Center for Visual Science, University of Rochester, Rochester, NY 14642, USA.
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3
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Penati S, Brioschi S, Cai Z, Han CZ, Colonna M. Mechanisms and environmental factors shaping the ecosystem of brain macrophages. Front Immunol 2025; 16:1539988. [PMID: 39925814 PMCID: PMC11802581 DOI: 10.3389/fimmu.2025.1539988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 01/03/2025] [Indexed: 02/11/2025] Open
Abstract
Brain macrophages encompass two major populations: microglia in the parenchyma and border-associated macrophages (BAMs) in the extra-parenchymal compartments. These cells play crucial roles in maintaining brain homeostasis and immune surveillance. Microglia and BAMs are phenotypically and epigenetically distinct and exhibit highly specialized functions tailored to their environmental niches. Intriguingly, recent studies have shown that both microglia and BAMs originate from the same myeloid progenitor during yolk sac hematopoiesis, but their developmental fates diverge within the brain. Several works have partially unveiled the mechanisms orchestrating the development of microglia and BAMs in both mice and humans; however, many questions remain unanswered. Defining the molecular underpinnings controlling the transcriptional and epigenetic programs of microglia and BAMs is one of the upcoming challenges for the field. In this review, we outline current knowledge on ontogeny, phenotypic diversity, and the factors shaping the ecosystem of brain macrophages. We discuss insights garnered from human studies, highlighting similarities and differences compared to mice. Lastly, we address current research gaps and potential future directions in the field. Understanding how brain macrophages communicate with their local environment and how the tissue instructs their developmental trajectories and functional features is essential to fully comprehend brain physiology in homeostasis and disease.
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Affiliation(s)
- Silvia Penati
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
| | - Simone Brioschi
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
| | - Zhangying Cai
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
| | - Claudia Z. Han
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
- Brain Immunology and Glia (BIG) Center, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
- Brain Immunology and Glia (BIG) Center, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
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4
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Gharibani P, Abramson E, Shanmukha S, Smith MD, Godfrey WH, Lee JJ, Hu J, Baydyuk M, Dorion MF, Deng X, Guo Y, Calle AJ, A Hwang S, Huang JK, Calabresi PA, Kornberg MD, Kim PM. The protein kinase C modulator bryostatin-1 therapeutically targets microglia to attenuate neuroinflammation and promote remyelination. Sci Transl Med 2025; 17:eadk3434. [PMID: 39772770 DOI: 10.1126/scitranslmed.adk3434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/19/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025]
Abstract
In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance among demyelination, neurodegeneration, and myelin repair. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the lack of therapies aimed at promoting remyelination and slowing disease progression for individuals with MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, shifts the transcriptional programs of microglia and CNS-associated macrophages from a proinflammatory phenotype to a regenerative phenotype in vitro and in vivo. Treatment of microglia with bryo-1 stimulated scavenger pathways, phagocytosis, and secretion of factors that prevented the activation of neuroinflammatory reactive astrocytes while also promoting neuroaxonal health and oligodendrocyte differentiation. In line with these findings, systemic treatment of mice with bryo-1 augmented remyelination after a focal demyelinating injury. Our results demonstrate the potential of bryo-1 and possibly a wider class of PKC modulators as myelin-regenerative and supportive agents in MS and other neurologic diseases.
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Affiliation(s)
- Payam Gharibani
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Efrat Abramson
- Interdepartmental Neuroscience Program, Yale University School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Shruthi Shanmukha
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Matthew D Smith
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Wesley H Godfrey
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Judy J Lee
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jingwen Hu
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Biology, Georgetown University, Washington, DC 20057, USA
| | - Maryna Baydyuk
- Department of Biology, Georgetown University, Washington, DC 20057, USA
| | - Marie-France Dorion
- Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada
| | - Xiaojing Deng
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Yu Guo
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Andrew J Calle
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Soonmyung A Hwang
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jeffrey K Huang
- Department of Biology, Georgetown University, Washington, DC 20057, USA
| | - Peter A Calabresi
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Michael D Kornberg
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Paul M Kim
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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5
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Zheng F, Dong T, Chen Y, Wang L, Peng G. Border-associated macrophages: From physiology to therapeutic targets in Alzheimer's disease. Exp Neurol 2025; 383:115021. [PMID: 39461707 DOI: 10.1016/j.expneurol.2024.115021] [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: 06/27/2024] [Revised: 10/15/2024] [Accepted: 10/20/2024] [Indexed: 10/29/2024]
Abstract
Border-associated macrophages (BAMs) constitute a highly heterogeneous group of central nervous system-resident macrophages at the brain boundaries. Despite their significance, BAMs have mainly been overlooked compared to microglia, resulting in a limited understanding of their functions. However, recent advancements in single-cell immunophenotyping and transcriptomic analyses of BAMs have revealed a previously unrecognized complexity in these cells, in addition to their critical roles under non-pathological conditions and diseases like Alzheimer's disease (AD), Parkinson's disease, glioma, and ischemic stroke. In this review, we discuss the origins, self-renewal capabilities, and extensive heterogeneity of BAMs, and clarify their important physiological functions such as immune monitoring, waste removal and vascular permeability regulation. We also summarize experimental evidence linking BAMs to the progression of AD. Finally, we review therapeutic strategies targeting brain innate immune cells mainly focusing on strategies aimed at modulating BAMs to treat AD and evaluate their potential in clinical applications.
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Affiliation(s)
- Fangxue Zheng
- Department of Neurology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Taiwei Dong
- Hangzhou Normal University School of Basic Medical Sciences, Hangzhou, China
| | - Yi Chen
- Department of Neurology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Lang Wang
- Department of Neurology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou, China.
| | - Guoping Peng
- Department of Neurology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
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6
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Bijnen M, Sridhar S, Keller A, Greter M. Brain macrophages in vascular health and dysfunction. Trends Immunol 2025; 46:46-60. [PMID: 39732528 DOI: 10.1016/j.it.2024.11.012] [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: 10/03/2024] [Revised: 11/08/2024] [Accepted: 11/19/2024] [Indexed: 12/30/2024]
Abstract
Diverse macrophage populations inhabit the rodent and human central nervous system (CNS), including microglia in the parenchyma and border-associated macrophages (BAMs) in the meninges, choroid plexus, and perivascular spaces. These innate immune phagocytes are essential in brain development and maintaining homeostasis, but they also play diverse roles in neurological diseases. In this review, we highlight the emerging roles of CNS macrophages in regulating vascular function in health and disease. We discuss that, in addition to microglia, BAMs, including perivascular macrophages, play roles in supporting vascular integrity and maintaining blood flow. We highlight recent advancements in understanding how these macrophages are implicated in protecting against vascular dysfunction and modulating the progression of cerebrovascular diseases, as seen in vessel-associated neurodegeneration.
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Affiliation(s)
- Mitchell Bijnen
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Sucheta Sridhar
- Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
| | - Annika Keller
- Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
| | - Melanie Greter
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
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7
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Chen Z, Zuo Z, Zhang Y, Shan G, Zhang L, Gong M, Ye Y, Ma Y, Jin Y. Bibliometric Analysis of Neuroinflammation and Postoperative Cognitive Dysfunction. Brain Behav 2025; 15:e70271. [PMID: 39789906 PMCID: PMC11726684 DOI: 10.1002/brb3.70271] [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: 08/07/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND The occurrence and development of postoperative cognitive dysfunction (POCD) are closely linked to neuroinflammation. This bibliometric analysis aims to provide novel insights into the research trajectory, key research topics, and potential future development trends in the field of neuroinflammation-induced POCD. METHODS The Web of Science Core Collection (WoSCC) database was searched to identify publications from 2012 to 2023 on neuroinflammation-induced POCD. Bibliometric analysis, involving both statistical and visual analyses, was conducted using CiteSpace, VOSviewer, and the R software. RESULTS Research on neuroinflammation-induced POCD has exhibited an increasing trend over the past 12 years. China had the highest number of publications, Nanjing Medical University had the most collaboration with other institutions, Zhiyi Zuo was the most published author, and the Journal of Neuroinflammation served as the primary publication in the field of neuroinflammation-induced POCD. The most frequent keyword was POCD. Keyword clustering analysis indicated that the predominant cluster is dexmedetomidine. Burst detection revealed that postoperative delirium (POD), perioperative neurocognitive disorders (PND), apoptosis, and epigenetic modifications were the future research trends. CONCLUSIONS Our analysis identified the following key research areas associated with neuroinflammation-induced POCD: anesthesia, surgery, dexmedetomidine, NLRP3 inflammasome, and mechanism of neuroinflammation-induced POCD. The potential future research topics comprise POD, PND, apoptosis, and epigenetic modifications.
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Affiliation(s)
- Zheping Chen
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain‐Like Intelligence, Clinical Research Center for Anesthesiology and Perioperative Medicine, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of MedicineTongji UniversityShanghaiPeople's Republic of China
- Department of Anesthesiology, the Second Hospital, Cheeloo College of MedicineShandong UniversityJinanPeople's Republic of China
| | - Zhenxiang Zuo
- Department of Gastroenterology, the Second Hospital, Cheeloo College of MedicineShandong UniversityJinanPeople's Republic of China
| | - Yizheng Zhang
- Department of Anesthesiology, the Second Hospital, Cheeloo College of MedicineShandong UniversityJinanPeople's Republic of China
| | - Guoliang Shan
- Department of Anesthesiology, the Second Hospital, Cheeloo College of MedicineShandong UniversityJinanPeople's Republic of China
| | - Le Zhang
- Department of Anesthesiology, the Second Hospital, Cheeloo College of MedicineShandong UniversityJinanPeople's Republic of China
| | - Moxuan Gong
- Department of Anesthesiology, the Second Hospital, Cheeloo College of MedicineShandong UniversityJinanPeople's Republic of China
| | - Yuyang Ye
- Department of Anesthesiology, the Second Hospital, Cheeloo College of MedicineShandong UniversityJinanPeople's Republic of China
| | - Yufeng Ma
- Department of Anesthesiology, the Second Hospital, Cheeloo College of MedicineShandong UniversityJinanPeople's Republic of China
| | - Yanwu Jin
- Department of Anesthesiology, the Second Hospital, Cheeloo College of MedicineShandong UniversityJinanPeople's Republic of China
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8
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Meng J, Zhang L, Zhang YW. Microglial Dysfunction in Autism Spectrum Disorder. Neuroscientist 2024; 30:744-758. [PMID: 38712859 DOI: 10.1177/10738584241252576] [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] [Indexed: 05/08/2024]
Abstract
Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with onset in childhood. The molecular mechanisms underlying ASD have not yet been elucidated completely. Evidence has emerged to support a link between microglial dysfunction and the etiology of ASD. This review summarizes current research on microglial dysfunction in neuroinflammation and synaptic pruning, which are associated with altered transcriptomes and autophagy in ASD. Dysbiosis of gut microbiota in ASD and its correlation with microglial dysfunction are also addressed.
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Affiliation(s)
- Jian Meng
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Lingliang Zhang
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Yun-Wu Zhang
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
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9
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Sabogal-Guaqueta AM, Mitchell-Garcia T, Hunneman J, Voshart D, Thiruvalluvan A, Foijer F, Kruyt F, Trombetta-Lima M, Eggen BJL, Boddeke E, Barazzuol L, Dolga AM. Brain organoid models for studying the function of iPSC-derived microglia in neurodegeneration and brain tumours. Neurobiol Dis 2024; 203:106742. [PMID: 39581553 DOI: 10.1016/j.nbd.2024.106742] [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: 09/30/2024] [Revised: 11/17/2024] [Accepted: 11/19/2024] [Indexed: 11/26/2024] Open
Abstract
Microglia represent the main resident immune cells of the brain. The interplay between microglia and other cells in the central nervous system, such as neurons or other glial cells, influences the function and ability of microglia to respond to various stimuli. These cellular communications, when disrupted, can affect the structure and function of the brain, and the initiation and progression of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, as well as the progression of other brain diseases like glioblastoma. Due to the difficult access to patient brain tissue and the differences reported in the murine models, the available models to study the role of microglia in disease progression are limited. Pluripotent stem cell technology has facilitated the generation of highly complex models, allowing the study of control and patient-derived microglia in vitro. Moreover, the ability to generate brain organoids that can mimic the 3D tissue environment and intercellular interactions in the brain provide powerful tools to study cellular pathways under homeostatic conditions and various disease pathologies. In this review, we summarise the most recent developments in modelling degenerative diseases and glioblastoma, with a focus on brain organoids with integrated microglia. We provide an overview of the most relevant research on intercellular interactions of microglia to evaluate their potential to study brain pathologies.
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Affiliation(s)
- Angelica Maria Sabogal-Guaqueta
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, The Netherlands.
| | - Teresa Mitchell-Garcia
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, The Netherlands
| | - Jasmijn Hunneman
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, The Netherlands
| | - Daniëlle Voshart
- Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
| | - Arun Thiruvalluvan
- European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Floris Foijer
- European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Frank Kruyt
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Marina Trombetta-Lima
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, The Netherlands; Faculty of Science and Engineering, Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, The Netherlands
| | - Bart J L Eggen
- Department of Biomedical Sciences, Section of Molecular Neurobiology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands
| | - Erik Boddeke
- Department of Biomedical Sciences, Section of Molecular Neurobiology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands
| | - Lara Barazzuol
- Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
| | - Amalia M Dolga
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, The Netherlands; Department Pathology and Medical biology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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10
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Toledano A, Rodríguez-Casado A, Älvarez MI, Toledano-Díaz A. Alzheimer's Disease, Obesity, and Type 2 Diabetes: Focus on Common Neuroglial Dysfunctions (Critical Review and New Data on Human Brain and Models). Brain Sci 2024; 14:1101. [PMID: 39595866 PMCID: PMC11591712 DOI: 10.3390/brainsci14111101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/17/2024] [Accepted: 10/24/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Obesity, type 2 diabetes (T2D), and Alzheimer's disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy and are difficult to prevent and control when they develop. It has been known for many years that these diseases have many pathogenic aspects in common. We highlight in this review that neuroglial cells (astroglia, oligodendroglia, and microglia) play a vital role in the origin, clinical-pathological development, and course of brain neurodegeneration. Moreover, we include the new results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we are investigating. METHODS Critical bibliographic revision and biochemical neuropathological study of neuroglia in a T2D-AD model. RESULTS T2D and AD are not only "connected" by producing complex pathologies in the same individual (obesity, T2D, and AD), but they also have many common pathogenic mechanisms. These include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, mitochondrial dysfunction, and inflammation (both peripheral and central-or neuroinflammation). Cognitive impairment and AD are the maximum exponents of brain neurodegeneration in these pathological processes. both due to the dysfunctions induced by metabolic changes in peripheral tissues and inadequate neurotoxic responses to changes in the brain. In this review, we first analyze the common pathogenic mechanisms of obesity, T2D, and AD (and/or cerebral vascular dementia) that induce transcendental changes and responses in neuroglia. The relationships between T2D and AD discussed mainly focus on neuroglial responses. Next, we present neuroglial changes within their neuropathological context in diverse scenarios: (a) aging involution and neurodegenerative disorders, (b) human obesity and diabetes and obesity/diabetes models, (c) human AD and in AD models, and (d) human AD-T2D and AD-T2D models. An important part of the data presented comes from our own studies on humans and experimental models over the past few years. In the T2D-AD section, we included the results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we investigated, which showed that neuroglial dysfunctions (astrocytosis and microgliosis) manifest before the appearance of amyloid neuropathology, and that the amyloid pathology is greater than that presented by mice fed a normal, non-high-caloric diet A broad review is finally included on pharmacological, cellular, genic, and non-pharmacological (especially diet and lifestyle) neuroglial-related treatments, as well as clinical trials in a comparative way between T2D and AD. These neuroglial treatments need to be included in the multimodal/integral treatments of T2D and AD to achieve greater therapeutic efficacy in many millions of patients. CONCLUSIONS Neuroglial alterations (especially in astroglia and microglia, cornerstones of neuroinflammation) are markedly defining brain neurodegeneration in T2D and A, although there are some not significant differences between each of the studied pathologies. Neuroglial therapies are a very important and p. promising tool that are being developed to prevent and/or treat brain dysfunction in T2D-AD. The need for further research in two very different directions is evident: (a) characterization of the phenotypic changes of astrocytes and microglial cells in each region of the brain and in each phase of development of each isolated and associated pathology (single-cell studies are mandatory) to better understand the pathologies and define new therapeutic targets; (b) studying new therapeutic avenues to normalize the function of neuroglial cells (preventing neurotoxic responses and/or reversing them) in these pathologies, as well as the phenotypic characteristics in each moment of the course and place of the neurodegenerative process.
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Affiliation(s)
- Adolfo Toledano
- Instituto Cajal, CSIC, 28002 Madrid, Spain; (A.R.-C.); (M.I.Ä.)
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11
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Bartos LM, Kunte ST, Wagner S, Beumers P, Schaefer R, Zatcepin A, Li Y, Griessl M, Hoermann L, Wind-Mark K, Bartenstein P, Tahirovic S, Ziegler S, Brendel M, Gnörich J. Astroglial glucose uptake determines brain FDG-PET alterations and metabolic connectivity during healthy aging in mice. Neuroimage 2024; 300:120860. [PMID: 39332748 DOI: 10.1016/j.neuroimage.2024.120860] [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: 07/16/2024] [Revised: 08/24/2024] [Accepted: 09/18/2024] [Indexed: 09/29/2024] Open
Abstract
PURPOSE 2-Fluorodeoxyglucose-PET (FDG-PET) is a powerful tool to study glucose metabolism in mammalian brains, but cellular sources of glucose uptake and metabolic connectivity during aging are not yet understood. METHODS Healthy wild-type mice of both sexes (2-21 months of age) received FDG-PET and cell sorting after in vivo tracer injection (scRadiotracing). FDG uptake per cell was quantified in isolated microglia, astrocytes and neurons. Cerebral FDG uptake and metabolic connectivity were determined by PET. A subset of mice received measurement of blood glucose levels to study associations with cellular FDG uptake during aging. RESULTS Cerebral FDG-PET signals in healthy mice increased linearly with age. Cellular FDG uptake of neurons increased between 2 and 12 months of age, followed by a strong decrease towards late ages. Contrarily, FDG uptake in microglia and astrocytes exhibited a U-shaped function with respect to age, comprising the predominant cellular source of higher cerebral FDG uptake in the later stages. Metabolic connectivity was closely associated with the ratio of glucose uptake in astroglial cells relative to neurons. Cellular FDG uptake was not associated with blood glucose levels and increasing FDG brain uptake as a function of age was still observed after adjusting for blood glucose levels. CONCLUSION Trajectories of astroglial glucose uptake drive brain FDG-PET alterations and metabolic connectivity during aging.
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Affiliation(s)
- Laura M Bartos
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Sebastian T Kunte
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Stephan Wagner
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Philipp Beumers
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Rebecca Schaefer
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Artem Zatcepin
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Germany
| | - Yunlei Li
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Maria Griessl
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Leonie Hoermann
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Karin Wind-Mark
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Germany
| | - Peter Bartenstein
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Sabina Tahirovic
- German Center for Neurodegenerative Diseases (DZNE) Munich, Germany
| | - Sibylle Ziegler
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Matthias Brendel
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Johannes Gnörich
- Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Germany.
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12
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Mirarchi A, Albi E, Arcuri C. Microglia Signatures: A Cause or Consequence of Microglia-Related Brain Disorders? Int J Mol Sci 2024; 25:10951. [PMID: 39456734 PMCID: PMC11507570 DOI: 10.3390/ijms252010951] [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: 08/09/2024] [Revised: 09/26/2024] [Accepted: 10/01/2024] [Indexed: 10/28/2024] Open
Abstract
Microglia signatures refer to distinct gene expression profiles or patterns of gene activity that are characteristic of microglia. Advances in gene expression profiling techniques, such as single-cell RNA sequencing, have allowed us to study microglia at a more detailed level and identify unique gene expression patterns that are associated, but not always, with different functional states of these cells. Microglial signatures depend on the developmental stage, brain region, and specific pathological conditions. By studying these signatures, it has been possible to gain insights into the underlying mechanisms of microglial activation and begin to develop targeted therapies to modulate microglia-mediated immune responses in the CNS. Historically, the first two signatures coincide with M1 pro-inflammatory and M2 anti-inflammatory phenotypes. The first one includes upregulation of genes such as CD86, TNF-α, IL-1β, and iNOS, while the second one may involve genes like CD206, Arg1, Chil3, and TGF-β. However, it has long been known that many and more specific phenotypes exist between M1 and M2, likely with corresponding signatures. Here, we discuss specific microglial signatures and their association, if any, with neurodegenerative pathologies and other brain disorders.
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Affiliation(s)
- Alessandra Mirarchi
- Department of Medicine and Surgery, University of Perugia, Piazza L. Severi 1, 06132 Perugia, Italy;
| | - Elisabetta Albi
- Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, Italy;
| | - Cataldo Arcuri
- Department of Medicine and Surgery, University of Perugia, Piazza L. Severi 1, 06132 Perugia, Italy;
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13
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Luczak-Sobotkowska ZM, Rosa P, Lopez MB, Ochocka N, Kiryk A, Lenkiewicz AM, Furhmann M, Jankowski A, Kaminska B. Tracking changes in functionality and morphology of repopulated microglia in young and old mice. J Neuroinflammation 2024; 21:248. [PMID: 39363245 PMCID: PMC11448401 DOI: 10.1186/s12974-024-03242-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/23/2024] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND Microglia (MG) are myeloid cells of the central nervous system that support homeostasis and instigate neuroinflammation in pathologies. Single-cell RNA sequencing (scRNA-seq) revealed the functional heterogeneity of MG in mouse brains. Microglia are self-renewing cells and inhibition of colony-stimulating factor 1 receptor (CSF1R) signaling depletes microglia which rapidly repopulate. The functions of repopulated microglia are poorly known. METHODS We combined scRNA-seq, bulk RNA-seq, immunofluorescence, and confocal imaging to study the functionalities and morphology of repopulated microglia. RESULTS A CSRF1R inhibitor (BLZ-945) depleted microglia within 21 days and a number of microglia was fully restored within 7 days, as confirmed by TMEM119 staining and flow cytometry. ScRNA-seq and computational analyses demonstrate that repopulated microglia originated from preexisting progenitors and reconstituted functional clusters but upregulated inflammatory genes. Percentages of proliferating, immature microglia displaying inflammatory gene expression increased in aging mice. Morphometric analysis of MG cell body and branching revealed a distinct morphology of repopulated MG, particularly in brains of old mice. We demonstrate that with aging some repopulated MG fail to reach the homeostatic phenotype. These differences may contribute to the deterioration of MG protective functions with age.
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Affiliation(s)
| | - Patrycja Rosa
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
- Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, Warsaw, Poland
| | - Maria Banqueri Lopez
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Natalia Ochocka
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Anna Kiryk
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Anna M Lenkiewicz
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Martin Furhmann
- Neuroimmunology and Imaging Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Aleksander Jankowski
- Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, Warsaw, Poland.
| | - Bozena Kaminska
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
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14
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Lopez-Ortiz AO, Eyo UB. Astrocytes and microglia in the coordination of CNS development and homeostasis. J Neurochem 2024; 168:3599-3614. [PMID: 37985374 PMCID: PMC11102936 DOI: 10.1111/jnc.16006] [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: 08/31/2023] [Revised: 10/20/2023] [Accepted: 10/20/2023] [Indexed: 11/22/2023]
Abstract
Glia have emerged as important architects of central nervous system (CNS) development and maintenance. While traditionally glial contributions to CNS development and maintenance have been studied independently, there is growing evidence that either suggests or documents that glia may act in coordinated manners to effect developmental patterning and homeostatic functions in the CNS. In this review, we focus on astrocytes, the most abundant glia in the CNS, and microglia, the earliest glia to colonize the CNS highlighting research that documents either suggestive or established coordinated actions by these glial cells in various CNS processes including cell and/or debris clearance, neuronal survival and morphogenesis, synaptic maturation, and circuit function, angio-/vasculogenesis, myelination, and neurotransmission. Some molecular mechanisms underlying these processes that have been identified are also described. Throughout, we categorize the available evidence as either suggestive or established interactions between microglia and astrocytes in the regulation of the respective process and raise possible avenues for further research. We conclude indicating that a better understanding of coordinated astrocyte-microglial interactions in the developing and mature brain holds promise for developing effective therapies for brain pathologies where these processes are perturbed.
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Affiliation(s)
- Aída Oryza Lopez-Ortiz
- Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, Virginia, USA
- Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia, USA
- Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Ukpong B Eyo
- Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, Virginia, USA
- Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia, USA
- Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, Virginia, USA
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15
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Hoffmann A, Miron VE. CNS macrophage contributions to myelin health. Immunol Rev 2024; 327:53-70. [PMID: 39484853 DOI: 10.1111/imr.13416] [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] [Indexed: 11/03/2024]
Abstract
Myelin is the membrane surrounding neuronal axons in the central nervous system (CNS), produced by oligodendrocytes to provide insulation for electrical impulse conduction and trophic/metabolic support. CNS dysfunction occurs following poor development of myelin in infancy, myelin damage in neurological diseases, and impaired regeneration of myelin with disease progression in aging. The lack of approved therapies aimed at supporting myelin health highlights the critical need to identify the cellular and molecular influences on oligodendrocytes. CNS macrophages have been shown to influence the development, maintenance, damage and regeneration of myelin, revealing critical interactions with oligodendrocyte lineage cells. CNS macrophages are comprised of distinct populations, including CNS-resident microglia and cells associated with CNS border regions (the meninges, vasculature, and choroid plexus), in addition to macrophages derived from monocytes infiltrating from the blood. Importantly, the distinct contribution of these macrophage populations to oligodendrocyte lineage responses and myelin health are only just beginning to be uncovered, with the advent of new tools to specifically identify, track, and target macrophage subsets. Here, we summarize the current state of knowledge on the roles of CNS macrophages in myelin health, and recent developments in distinguishing the roles of macrophage populations in development, homeostasis, and disease.
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Affiliation(s)
- Alana Hoffmann
- BARLO Multiple Sclerosis Centre and Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada
- Department of Immunology, The University of Toronto, Toronto, Ontario, Canada
- United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh, UK
- Centre for Discovery Brain Sciences, Chancellor's Building, The University of Edinburgh, Edinburgh, UK
| | - Veronique E Miron
- BARLO Multiple Sclerosis Centre and Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada
- Department of Immunology, The University of Toronto, Toronto, Ontario, Canada
- United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh, UK
- Centre for Discovery Brain Sciences, Chancellor's Building, The University of Edinburgh, Edinburgh, UK
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16
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Pramanik S, Devi M H, Chakrabarty S, Paylar B, Pradhan A, Thaker M, Ayyadhury S, Manavalan A, Olsson PE, Pramanik G, Heese K. Microglia signaling in health and disease - Implications in sex-specific brain development and plasticity. Neurosci Biobehav Rev 2024; 165:105834. [PMID: 39084583 DOI: 10.1016/j.neubiorev.2024.105834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 07/21/2024] [Accepted: 07/27/2024] [Indexed: 08/02/2024]
Abstract
Microglia, the intrinsic neuroimmune cells residing in the central nervous system (CNS), exert a pivotal influence on brain development, homeostasis, and functionality, encompassing critical roles during both aging and pathological states. Recent advancements in comprehending brain plasticity and functions have spotlighted conspicuous variances between male and female brains, notably in neurogenesis, neuronal myelination, axon fasciculation, and synaptogenesis. Nevertheless, the precise impact of microglia on sex-specific brain cell plasticity, sculpting diverse neural network architectures and circuits, remains largely unexplored. This article seeks to unravel the present understanding of microglial involvement in brain development, plasticity, and function, with a specific emphasis on microglial signaling in brain sex polymorphism. Commencing with an overview of microglia in the CNS and their associated signaling cascades, we subsequently probe recent revelations regarding molecular signaling by microglia in sex-dependent brain developmental plasticity, functions, and diseases. Notably, C-X3-C motif chemokine receptor 1 (CX3CR1), triggering receptors expressed on myeloid cells 2 (TREM2), calcium (Ca2+), and apolipoprotein E (APOE) emerge as molecular candidates significantly contributing to sex-dependent brain development and plasticity. In conclusion, we address burgeoning inquiries surrounding microglia's pivotal role in the functional diversity of developing and aging brains, contemplating their potential implications for gender-tailored therapeutic strategies in neurodegenerative diseases.
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Affiliation(s)
- Subrata Pramanik
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
| | - Harini Devi M
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Saswata Chakrabarty
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Berkay Paylar
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Ajay Pradhan
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Manisha Thaker
- Eurofins Lancaster Laboratories, Inc., 2425 New Holland Pike, Lancaster, PA 17601, USA
| | - Shamini Ayyadhury
- The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada
| | - Arulmani Manavalan
- Department of Cariology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu 600077, India
| | - Per-Erik Olsson
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Gopal Pramanik
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India.
| | - Klaus Heese
- Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133791, the Republic of Korea.
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17
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Samuels JD, Lukens JR, Price RJ. Emerging roles for ITAM and ITIM receptor signaling in microglial biology and Alzheimer's disease-related amyloidosis. J Neurochem 2024; 168:3558-3573. [PMID: 37822118 DOI: 10.1111/jnc.15981] [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: 08/07/2023] [Revised: 09/11/2023] [Accepted: 09/21/2023] [Indexed: 10/13/2023]
Abstract
Microglia are critical responders to amyloid beta (Aβ) plaques in Alzheimer's disease (AD). Therefore, the therapeutic targeting of microglia in AD is of high clinical interest. While previous investigation has focused on the innate immune receptors governing microglial functions in response to Aβ plaques, how microglial innate immune responses are regulated is not well understood. Interestingly, many of these microglial innate immune receptors contain unique cytoplasmic motifs, termed immunoreceptor tyrosine-based activating and inhibitory motifs (ITAM/ITIM), that are commonly known to regulate immune activation and inhibition in the periphery. In this review, we summarize the diverse functions employed by microglia in response to Aβ plaques and also discuss the innate immune receptors and intracellular signaling players that guide these functions. Specifically, we focus on the role of ITAM and ITIM signaling cascades in regulating microglia innate immune responses. A better understanding of how microglial innate immune responses are regulated in AD may provide novel therapeutic avenues to tune the microglial innate immune response in AD pathology.
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Affiliation(s)
- Joshua D Samuels
- Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia (UVA), Charlottesville, Virginia, USA
- Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia, USA
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
| | - John R Lukens
- Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia (UVA), Charlottesville, Virginia, USA
- Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia, USA
| | - Richard J Price
- Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia, USA
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
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18
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Haghshenas L, Banihashemi S, Malekzadegan Y, Catanzaro R, Moghadam Ahmadi A, Marotta F. Microbiome as an endocrine organ and its relationship with eye diseases: Effective factors and new targeted approaches. World J Gastrointest Pathophysiol 2024; 15:96446. [PMID: 39355345 PMCID: PMC11440246 DOI: 10.4291/wjgp.v15.i5.96446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 09/04/2024] [Accepted: 09/13/2024] [Indexed: 09/20/2024] Open
Abstract
Microbiome is an endocrine organ that refers to both the complicated biological system of microbial species that colonize our bodies and their genomes and surroundings. Recent studies confirm the connection between the microbiome and eye diseases, which are involved in the pathogenesis of eye diseases, including age-related macular disorders, diabetic retinopathy, glaucoma, retinitis pigmentosa, dry eye, and uveitis. The aim of this review is to investigate the microbiome in relation to eye health. First, a brief introduction of the characteristics of the gut microorganisms terms of composition and work, the role of dysbiosis, the gut microbiome and the eye microbiome in the progression of eye illnesses are highlighted, then the relationship among the microbiome and the function of the immune system and eye diseases, the role of inflammation and aging and the immune system, It has been reviewed and finally, the control and treatment goals of microbiome and eye diseases, the role of food factors and supplements, biotherapy and antibiotics in relation to microbiome and eye health have been reviewed.
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Affiliation(s)
- Leila Haghshenas
- Department of Clinical Bioinformatics, Harvard Medical School, Boston, MA 02115, United States
| | - Sara Banihashemi
- Department of Bioscience, School of Science and Technology, Nottingham Trend University, Nottingham NG1 4FQ, United Kingdom
| | - Yalda Malekzadegan
- Department of Microbiology, Saveh University of Medical Sciences, Saveh 3919676651, Iran
| | - Roberto Catanzaro
- Department of Clinical and Experimental Medicine, University of Catania, Catania 95123, Catania, Italy
| | - Amir Moghadam Ahmadi
- Department of Neuroimmunology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Francesco Marotta
- Department of Human Nutrition and Food Sciences, Texas Women University, Milano 20154, Italy
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Blazey T, Lee JJ, Snyder AZ, Goyal MS, Hershey T, Arbeláez AM, Raichle ME. Hyperglycemia selectively increases cerebral non-oxidative glucose consumption without affecting blood flow. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.05.611035. [PMID: 39314314 PMCID: PMC11418958 DOI: 10.1101/2024.09.05.611035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Multiple studies have shown that hyperglycemia increases the cerebral metabolic rate of glucose (CMRglc) in subcortical white matter. This observation remains unexplained. Using positron emission tomography (PET) and euinsulinaemic glucose clamps, we found, for the first time, that acute hyperglycemia increases non-oxidative CMRglc (i.e., aerobic glycolysis (AG)) in subcortical white mater as well as in medial temporal lobe structures, cerebellum and brainstem, all areas with low euglycemic CMRglc. Surprisingly, hyperglycemia did not change regional cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2), or the blood-oxygen-level-dependent (BOLD) response. Regional gene expression data reveal that brain regions where CMRglc increased have greater expression of hexokinase 2 (HK2). Simulations of glucose transport revealed that, unlike hexokinase 1, HK2 is not saturated at euglycemia, thus accommodating increased AG during hyperglycemia.
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Affiliation(s)
- Tyler Blazey
- Mallinckrodt Institute of Radiology, School of Medicine, Washington University, St. Louis, MO 63110, USA
| | - John J Lee
- Mallinckrodt Institute of Radiology, School of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Abraham Z Snyder
- Mallinckrodt Institute of Radiology, School of Medicine, Washington University, St. Louis, MO 63110, USA
- Department of Neurology, School of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Manu S Goyal
- Mallinckrodt Institute of Radiology, School of Medicine, Washington University, St. Louis, MO 63110, USA
- Department of Neurology, School of Medicine, Washington University, St. Louis, MO 63110, USA
- Department of Neuroscience, School of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Tamara Hershey
- Mallinckrodt Institute of Radiology, School of Medicine, Washington University, St. Louis, MO 63110, USA
- Department of Neurology, School of Medicine, Washington University, St. Louis, MO 63110, USA
- Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Ana Maria Arbeláez
- Department of Pediatrics, School of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Marcus E Raichle
- Mallinckrodt Institute of Radiology, School of Medicine, Washington University, St. Louis, MO 63110, USA
- Department of Neurology, School of Medicine, Washington University, St. Louis, MO 63110, USA
- Department of Neuroscience, School of Medicine, Washington University, St. Louis, MO 63110, USA
- Department of Biomedical Engineering, Washington University, St. Louis, MO 63105, USA
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20
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Ji Y, McLean JL, Xu R. Emerging Human Pluripotent Stem Cell-Based Human-Animal Brain Chimeras for Advancing Disease Modeling and Cell Therapy for Neurological Disorders. Neurosci Bull 2024; 40:1315-1332. [PMID: 38466557 PMCID: PMC11365908 DOI: 10.1007/s12264-024-01189-z] [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: 08/08/2023] [Accepted: 11/23/2023] [Indexed: 03/13/2024] Open
Abstract
Human pluripotent stem cell (hPSC) models provide unprecedented opportunities to study human neurological disorders by recapitulating human-specific disease mechanisms. In particular, hPSC-based human-animal brain chimeras enable the study of human cell pathophysiology in vivo. In chimeric brains, human neural and immune cells can maintain human-specific features, undergo maturation, and functionally integrate into host brains, allowing scientists to study how human cells impact neural circuits and animal behaviors. The emerging human-animal brain chimeras hold promise for modeling human brain cells and their interactions in health and disease, elucidating the disease mechanism from molecular and cellular to circuit and behavioral levels, and testing the efficacy of cell therapy interventions. Here, we discuss recent advances in the generation and applications of using human-animal chimeric brain models for the study of neurological disorders, including disease modeling and cell therapy.
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Affiliation(s)
- Yanru Ji
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Jenna Lillie McLean
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Ranjie Xu
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, 47907, USA.
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21
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Staels W, Berthault C, Bourgeois S, Laville V, Lourenço C, De Leu N, Scharfmann R. Comprehensive alpha, beta, and delta cell transcriptomics reveal an association of cellular aging with MHC class I upregulation. Mol Metab 2024; 87:101990. [PMID: 39009220 PMCID: PMC11327396 DOI: 10.1016/j.molmet.2024.101990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/09/2024] [Accepted: 07/09/2024] [Indexed: 07/17/2024] Open
Abstract
OBJECTIVES This study aimed to evaluate the efficacy of a purification method developed for isolating alpha, beta, and delta cells from pancreatic islets of adult mice, extending its application to islets from newborn and aged mice. Furthermore, it sought to examine transcriptome dynamics in mouse pancreatic endocrine islet cells throughout postnatal development and to validate age-related alterations within these cell populations. METHODS We leveraged the high surface expression of CD71 on beta cells and CD24 on delta cells to FACS-purify alpha, beta, and delta cells from newborn (1-week-old), adult (12-week-old), and old (18-month-old) mice. Bulk RNA sequencing was conducted on these purified cell populations, and subsequent bioinformatic analyses included differential gene expression, overrepresentation, and intersection analysis. RESULTS Alpha, beta, and delta cells from newborn and aged mice were successfully FACS-purified using the same method employed for adult mice. Our analysis of the age-related transcriptional changes in alpha, beta, and delta cell populations revealed a decrease in cell cycling and an increase in neuron-like features processes during the transition from newborn to adult mice. Progressing from adult to old mice, we identified an inflammatory gene signature related to aging (inflammaging) encompassing an increase in β-2 microglobulin and major histocompatibility complex (MHC) Class I expression. CONCLUSIONS Our study demonstrates the effectiveness of our cell sorting technique in purifying endocrine subsets from mouse islets at different ages. We provide a valuable resource for better understanding endocrine pancreas aging and identified an inflammaging gene signature with increased β-2 microglobulin and MHC Class I expression as a common hallmark of old alpha, beta, and delta cells, with potential implications for immune response regulation and age-related diabetes.
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Affiliation(s)
- W Staels
- Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, Paris, France; Genetics, Reproduction and Development (GRAD), Vrije Universiteit Brussel (VUB), Brussels, Belgium; Division of Pediatric Endocrinology, Department of Pediatrics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.
| | - C Berthault
- Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, Paris, France
| | - S Bourgeois
- Genetics, Reproduction and Development (GRAD), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - V Laville
- Stem Cells and Development Unit, Institut Pasteur, Paris, France; UMR CNRS 3738, Institut Pasteur, Paris, France; Université Paris Cité, Bioinformatics and Biostatistics Hub, Paris, France
| | - C Lourenço
- Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, Paris, France
| | - N De Leu
- Genetics, Reproduction and Development (GRAD), Vrije Universiteit Brussel (VUB), Brussels, Belgium; Endocrinology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium; Endocrinology, ASZ Aalst, 9300 Aalst, Belgium
| | - R Scharfmann
- Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, Paris, France
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22
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Vicario R, Fragkogianni S, Weber L, Lazarov T, Hu Y, Hayashi SY, Craddock BP, Socci ND, Alberdi A, Baako A, Ay O, Ogishi M, Lopez-Rodrigo E, Kappagantula R, Viale A, Iacobuzio-Donahue CA, Zhou T, Ransohoff RM, Chesworth R, Abdel-Wahab O, Boisson B, Elemento O, Casanova JL, Miller WT, Geissmann F. A microglia clonal inflammatory disorder in Alzheimer's Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.25.577216. [PMID: 38328106 PMCID: PMC10849735 DOI: 10.1101/2024.01.25.577216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however few studies have investigated its role in neurodegenerative processes such as Alzheimer's Disease (AD). Here we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in human, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.
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Affiliation(s)
- Rocio Vicario
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Stamatina Fragkogianni
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Leslie Weber
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Tomi Lazarov
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Yang Hu
- Department of Physiology and Biophysics, Institute for Computational Biomedicine,Weill Cornell New York, NY 10021, USA
| | - Samantha Y. Hayashi
- Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8661
| | - Barbara P. Craddock
- Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8661
| | - Nicholas D. Socci
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Araitz Alberdi
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Ann Baako
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Oyku Ay
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Masato Ogishi
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
| | - Estibaliz Lopez-Rodrigo
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Rajya Kappagantula
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Agnes Viale
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Christine A. Iacobuzio-Donahue
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Ting Zhou
- SKI Stem Cell Research Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | | | | | | | - Omar Abdel-Wahab
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
| | - Olivier Elemento
- Department of Physiology and Biophysics, Institute for Computational Biomedicine,Weill Cornell New York, NY 10021, USA
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
| | - W. Todd Miller
- Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8661
| | - Frederic Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
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23
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Camacho-Morales A, Cárdenas-Tueme M. Prenatal Programming of Monocyte Chemotactic Protein-1 Signaling in Autism Susceptibility. Mol Neurobiol 2024; 61:6119-6134. [PMID: 38277116 DOI: 10.1007/s12035-024-03940-z] [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: 09/12/2023] [Accepted: 01/11/2024] [Indexed: 01/27/2024]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that involves functional and structural defects in selective central nervous system (CNS) regions, harming the individual capability to process and respond to external stimuli, including impaired verbal and non-verbal communications. Etiological causes of ASD have not been fully clarified; however, prenatal activation of the innate immune system by external stimuli might infiltrate peripheral immune cells into the fetal CNS and activate cytokine secretion by microglia and astrocytes. For instance, genomic and postmortem histological analysis has identified proinflammatory gene signatures, microglia-related expressed genes, and neuroinflammatory markers in the brain during ASD diagnosis. Active neuroinflammation might also occur during the developmental stage, promoting the establishment of a defective brain connectome and increasing susceptibility to ASD after birth. While still under investigation, we tested the hypothesis whether the monocyte chemoattractant protein-1 (MCP-1) signaling is prenatally programmed to favor peripheral immune cell infiltration and activate microglia into the fetal CNS, setting susceptibility to autism-like behavior. In this review, we will comprehensively provide the current understanding of the prenatal activation of MCP-1 signaling by external stimuli during the developmental stage as a new selective node to promote neuroinflammation, brain structural alterations, and behavioral defects associated to ASD diagnosis.
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Affiliation(s)
- Alberto Camacho-Morales
- College of Medicine, Department of Biochemistry, Universidad Autónoma de Nuevo Leon, Monterrey, NL, Mexico.
- Center for Research and Development in Health Sciences, Neurometabolism Unit, Universidad Autónoma de Nuevo Leon, San Nicolás de los Garza, Monterrey, NL, Mexico.
| | - Marcela Cárdenas-Tueme
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de La Salud and The Institute for Obesity Research, 64710, Monterrey, Mexico
- Nutrition Unit, Center for Research and Development in Health Sciences, Universidad Autonoma de Nuevo Leon, 64460, Monterrey, Mexico
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24
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Sierra A, Miron VE, Paolicelli RC, Ransohoff RM. Microglia in Health and Diseases: Integrative Hubs of the Central Nervous System (CNS). Cold Spring Harb Perspect Biol 2024; 16:a041366. [PMID: 38438189 PMCID: PMC11293550 DOI: 10.1101/cshperspect.a041366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2024]
Abstract
Microglia are usually referred to as "the innate immune cells of the brain," "the resident macrophages of the central nervous system" (CNS), or "CNS parenchymal macrophages." These labels allude to their inherent immune function, related to their macrophage lineage. However, beyond their classic innate immune responses, microglia also play physiological roles crucial for proper brain development and maintenance of adult brain homeostasis. Microglia sense both external and local stimuli through a variety of surface receptors. Thus, they might serve as integrative hubs at the interface between the external environment and the CNS, able to decode, filter, and buffer cues from outside, with the aim of preserving and maintaining brain homeostasis. In this perspective, we will cast a critical look at how these multiple microglial functions are acquired and coordinated, and we will speculate on their impact on human brain physiology and pathology.
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Affiliation(s)
- Amanda Sierra
- Achucarro Basque Center for Neuroscience, Glial Cell Biology Laboratory, Science Park of UPV/EHU, E-48940 Leioa, Bizkaia, Spain
- Department of Biochemistry and Molecular Biology, University of the Basque Country EHU/UPV, 48940 Leioa, Spain
- Ikerbasque Foundation, Bilbao 48009, Spain
| | - Veronique E Miron
- BARLO Multiple Sclerosis Centre, Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto M5B 1T8, Canada
- Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada
- UK Dementia Research Institute at the University of Edinburgh, Edinburgh BioQuarter, Edinburgh EH16 4TJ, United Kingdom
| | - Rosa C Paolicelli
- Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, CH-1005 Lausanne, Switzerland
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25
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Mora-Romero B, Capelo-Carrasco N, Pérez-Moreno JJ, Alvarez-Vergara MI, Trujillo-Estrada L, Romero-Molina C, Martinez-Marquez E, Morano-Catalan N, Vizuete M, Lopez-Barneo J, Nieto-Gonzalez JL, Garcia-Junco-Clemente P, Vitorica J, Gutierrez A, Macias D, Rosales-Nieves AE, Pascual A. Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality. Nat Metab 2024; 6:1479-1491. [PMID: 39048800 DOI: 10.1038/s42255-024-01081-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/11/2024] [Indexed: 07/27/2024]
Abstract
Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.
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Affiliation(s)
- Bella Mora-Romero
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Department of Biología Celular, Facultad de Biología, Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Nicolas Capelo-Carrasco
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Department of Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain
| | - Juan J Pérez-Moreno
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
- Department of Biología Celular, Facultad de Biología, Universidad de Sevilla, Seville, Spain.
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
| | - María I Alvarez-Vergara
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Department of Biología Celular, Facultad de Biología, Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Institute for Neurovascular Cell Biology, University Hospital Bonn, Bonn, Germany
| | - Laura Trujillo-Estrada
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Department of Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigacion Biomedica de Malaga (IBIMA), Universidad de Málaga, Málaga, Spain
| | - Carmen Romero-Molina
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Department of Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Emilio Martinez-Marquez
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain
| | - Noelia Morano-Catalan
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Marisa Vizuete
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Department of Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain
| | - Jose Lopez-Barneo
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain
| | - Jose L Nieto-Gonzalez
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain
| | - Pablo Garcia-Junco-Clemente
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain
| | - Javier Vitorica
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Department of Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain
| | - Antonia Gutierrez
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Department of Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigacion Biomedica de Malaga (IBIMA), Universidad de Málaga, Málaga, Spain
| | - David Macias
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain
| | - Alicia E Rosales-Nieves
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Department of Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain
| | - Alberto Pascual
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
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26
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Yang D, Sun Y, Lin D, Li S, Zhang Y, Wu A, Wei C. Interleukin-33 ameliorates perioperative neurocognitive disorders by modulating microglial state. Neuropharmacology 2024; 253:109982. [PMID: 38701943 DOI: 10.1016/j.neuropharm.2024.109982] [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: 12/14/2023] [Revised: 04/16/2024] [Accepted: 04/30/2024] [Indexed: 05/06/2024]
Abstract
Perioperative neurocognitive disorders (PND) are cognitive dysfunctions that usually occur in elderly patients after anesthesia and surgery. Microglial overactivation is a key underlying mechanism. Interleukin-33 (IL-33) is a member of the IL-1 family that orchestrates microglial function. In the present study, we explored how IL-33, which regulates microglia, contributes to cognitive improvement in a male mouse model of PND. An exploratory laparotomy was performed to establish a PND model. The expression levels of IL-33 and its receptor ST2 were evaluated using Western blot. IL-33/ST2 secretion, microglial density, morphology, phagocytosis of synapse, and proliferation, and dystrophic microglia were assessed using immunofluorescence. Synaptic plasticity was measured using Golgi staining and long-term potentiation. The Morris water maze and open field test were used to evaluate cognitive function and anxiety. Hippocampal expression of IL-33 and ST2 were elevated on postoperative day 3. We confirmed that IL-33 was secreted by astrocytes and neurons, whereas ST2 mainly colocalized with microglia. IL-33 treatment induced microgliosis after anesthesia and surgery. These microglia had larger soma sizes and shorter and fragmented branches. Compared to the Surgery group, IL-33 treatment reduced the synaptic phagocytosis of microglia and increased microglial proliferation and dystrophic microglia. IL-33 treatment also reversed the impaired synaptic plasticity and cognitive function caused by anesthesia and surgery. In conclusion, these results indicate that IL-33 plays a key role in regulating microglial state and synaptic phagocytosis in a PND mouse model. IL-33 treatment has a therapeutic potential for improving cognitive dysfunction in PND.
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Affiliation(s)
- Di Yang
- Department of Anesthesiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yi Sun
- Department of Anesthesiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Dandan Lin
- Department of Anesthesiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Sijie Li
- Department of Anesthesiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yan Zhang
- State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, China.
| | - Anshi Wu
- Department of Anesthesiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
| | - Changwei Wei
- Department of Anesthesiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
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27
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Zhang Y, Li D, Gao H, Zhao H, Zhang S, Li T. Rapamycin Alleviates Neuronal Injury and Modulates Microglial Activation After Cerebral Ischemia. Mol Neurobiol 2024; 61:5699-5717. [PMID: 38224443 DOI: 10.1007/s12035-023-03904-9] [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: 10/03/2022] [Accepted: 12/21/2023] [Indexed: 01/16/2024]
Abstract
Neurons and microglia are sensitive to cerebral microcirculation and their responses play a crucial part in the pathological processes, while they are also the main target cells of many drugs used to treat brain diseases. Rapamycin exhibits beneficial effects in many diseases; however, whether it can affect neuronal injury or alter the microglial activation after global cerebral ischemia remains unclear. In this study, we performed global cerebral ischemia combined with rapamycin treatment in CX3CR1GFP/+ mice and explored the effects of rapamycin on neuronal deficit and microglial activation. Our results showed that rapamycin reduced neuronal loss, neurodegeneration, and ultrastructural damage after ischemia by histological staining and transmission electron microscopy (TEM). Interestingly, rapamycin suppressed de-ramification and proliferation of microglia and reduced the density of microglia. Immunofluorescence staining indicated that rapamycin skewed microglial polarization toward an anti-inflammatory state. Furthermore, rapamycin as well suppressed the activation of astrocytes. Meanwhile, quantitative real-time polymerase chain reaction (qRT-PCR) analyses revealed a significant reduction of pro-inflammatory factors as well as an elevation of anti-inflammatory factors upon rapamycin treatment. As a result of these effects, behavioral tests showed that rapamycin significantly alleviated the brain injury after stroke. Together, our study suggested that rapamycin attenuated neuronal injury, altered microglial activation state, and provided a more beneficial immune microenvironment for the brain, which could be used as a promising therapeutic approach to treat ischemic cerebrovascular diseases.
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Affiliation(s)
- Yue Zhang
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Donghai Li
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, China
| | - Hao Gao
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, China
| | - Haiyu Zhao
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, China
| | - Shengxiang Zhang
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, China.
| | - Ting Li
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, China.
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Vicario R, Fragkogianni S, Pokrovskii M, Mayer C, Lopez-Rodrigo E, Hu Y, Ogishi M, Alberdi A, Baako A, Ay O, Plu I, Sazdovitch V, Heritier S, Cohen-Aubart F, Shor N, Miyara M, Nguyen-Khac F, Viale A, Idbaih A, Amoura Z, Rosenblum MK, Zhang H, Karnoub ER, Sashittal P, Jakatdar A, Iacobuzio-Donahue CA, Abdel-Wahab O, Tabar V, Socci ND, Elemento O, Diamond EL, Boisson B, Casanova JL, Seilhean D, Haroche J, Donadieu J, Geissmann F. Mechanism of neurodegeneration mediated by clonal inflammatory microglia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.30.605867. [PMID: 39131366 PMCID: PMC11312538 DOI: 10.1101/2024.07.30.605867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1+ microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1+ clones (p= 0.0003). Genetic lineage tracing of PU.1+ clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.
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Affiliation(s)
- Rocio Vicario
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Stamatina Fragkogianni
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Maria Pokrovskii
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Carina Mayer
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Estibaliz Lopez-Rodrigo
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Yang Hu
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell New York, NY 10021, USA
| | - Masato Ogishi
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
| | - Araitz Alberdi
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Ann Baako
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Oyku Ay
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Isabelle Plu
- Department of Neuropathology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Véronique Sazdovitch
- Department of Neuropathology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Sebastien Heritier
- French Langerhans cell histiocytosis registry, Department of Pediatric Hematology and Oncology, Trousseau Hospital, AP-HP, Paris, France
| | - Fleur Cohen-Aubart
- Department of Internal Medicine & Institut E3M, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Natalia Shor
- Department of Neuroradiology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Makoto Miyara
- Center for Immunology and Infectious Diseases (CIMI-PARIS), Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Florence Nguyen-Khac
- Department of Hematology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Agnes Viale
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, MSKCC, New York, New York 10065, USA
| | - Ahmed Idbaih
- Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, F-75013, Paris, France
| | - Zahir Amoura
- Department of Neuroradiology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | | | - Haochen Zhang
- Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA)
| | | | | | | | - Christine A. Iacobuzio-Donahue
- Department of Pathology, MSKCC, New York, New York 10065, USA
- Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA)
| | - Omar Abdel-Wahab
- Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA)
| | - Viviane Tabar
- Department of Neurosurgery, and Center for Stem Cell Biology, MSKCC, New York, NY, USA
- Department of Neurology, MSKCC, New York, New York 10065, USA
| | - Nicholas D. Socci
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, MSKCC, New York, New York 10065, USA
| | - Olivier Elemento
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell New York, NY 10021, USA
| | - Eli L Diamond
- Department of Neurosurgery, and Center for Stem Cell Biology, MSKCC, New York, NY, USA
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
| | - Danielle Seilhean
- Department of Neuropathology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Julien Haroche
- Department of Internal Medicine & Institut E3M, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Jean Donadieu
- French Langerhans cell histiocytosis registry, Department of Pediatric Hematology and Oncology, Trousseau Hospital, AP-HP, Paris, France
| | - Frederic Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
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29
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Nevelchuk S, Brawek B, Schwarz N, Valiente-Gabioud A, Wuttke TV, Kovalchuk Y, Koch H, Höllig A, Steiner F, Figarella K, Griesbeck O, Garaschuk O. Morphotype-specific calcium signaling in human microglia. J Neuroinflammation 2024; 21:175. [PMID: 39020359 PMCID: PMC11256502 DOI: 10.1186/s12974-024-03169-6] [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: 05/25/2024] [Accepted: 07/09/2024] [Indexed: 07/19/2024] Open
Abstract
BACKGROUND Key functions of Ca2+ signaling in rodent microglia include monitoring the brain state as well as the surrounding neuronal activity and sensing the danger or damage in their vicinity. Microglial Ca2+ dyshomeostasis is a disease hallmark in many mouse models of neurological disorders but the Ca2+ signal properties of human microglia remain unknown. METHODS We developed a novel genetically-encoded ratiometric Ca2+ indicator, targeting microglial cells in the freshly resected human tissue, organotypically cultured tissue slices and analyzed in situ ongoing Ca2+ signaling of decades-old microglia dwelling in their native microenvironment. RESULTS The data revealed marked compartmentalization of Ca2+ signals, with signal properties differing across the compartments and resident morphotypes. The basal Ca2+ levels were low in ramified and high in ameboid microglia. The fraction of cells with ongoing Ca2+ signaling, the fraction and the amplitude of process Ca2+ signals and the duration of somatic Ca2+ signals decreased when moving from ramified via hypertrophic to ameboid microglia. In contrast, the size of active compartments, the fraction and amplitude of somatic Ca2+ signals and the duration of process Ca2+ signals increased along this pathway.
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Affiliation(s)
- Sofia Nevelchuk
- Department of Neurophysiology, Institute of Physiology, Eberhard Karls University of Tübingen, Keplerstr. 15, 72074, Tübingen, Germany
| | - Bianca Brawek
- Department of Neurophysiology, Institute of Physiology, Eberhard Karls University of Tübingen, Keplerstr. 15, 72074, Tübingen, Germany
| | - Niklas Schwarz
- Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Ariel Valiente-Gabioud
- Tools for Bio-Imaging, Max-Planck-Institute for Biological Intelligence, Martinsried, Germany
| | - Thomas V Wuttke
- Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
- Department of Neurosurgery, University of Tübingen, Tübingen, Germany
| | - Yury Kovalchuk
- Department of Neurophysiology, Institute of Physiology, Eberhard Karls University of Tübingen, Keplerstr. 15, 72074, Tübingen, Germany
| | - Henner Koch
- Department of Epileptology, Neurology, RWTH Aachen University Hospital, Aachen, Germany
| | - Anke Höllig
- Department of Neurosurgery, RWTH Aachen University, Aachen, Germany
| | - Frederik Steiner
- Department of Neurophysiology, Institute of Physiology, Eberhard Karls University of Tübingen, Keplerstr. 15, 72074, Tübingen, Germany
| | - Katherine Figarella
- Department of Neurophysiology, Institute of Physiology, Eberhard Karls University of Tübingen, Keplerstr. 15, 72074, Tübingen, Germany
- Department of Anesthesiology, Critical Care and Pain Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Oliver Griesbeck
- Tools for Bio-Imaging, Max-Planck-Institute for Biological Intelligence, Martinsried, Germany
| | - Olga Garaschuk
- Department of Neurophysiology, Institute of Physiology, Eberhard Karls University of Tübingen, Keplerstr. 15, 72074, Tübingen, Germany.
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30
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Weindel CG, Ellzey LM, Coleman AK, Patrick KL, Watson RO. LRRK2 kinase activity restricts NRF2-dependent mitochondrial protection in microglia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.09.602769. [PMID: 39026883 PMCID: PMC11257505 DOI: 10.1101/2024.07.09.602769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Mounting evidence supports a critical role for central nervous system (CNS) glial cells in neuroinflammation and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), as well as neurovascular ischemic stroke. Previously, we found that loss of the PD-associated gene leucine-rich repeat kinase 2 (Lrrk2) in macrophages, peripheral innate immune cells, induced mitochondrial stress and elevated basal expression of type I interferon (IFN) stimulated genes (ISGs) due to chronic mitochondrial DNA engagement with the cGAS/STING DNA sensing pathway. Here, we report that loss of LRRK2 results in a paradoxical response in microglial cells, a CNS-specific macrophage population. In primary murine microglia and microglial cell lines, loss of Lrrk2 reduces tonic IFN signaling leading to a reduction in ISG expression. Consistent with reduced type I IFN, mitochondria from Lrrk2 KO microglia are protected from stress and have elevated metabolism. These protective phenotypes involve upregulation of NRF2, an important transcription factor in the response to oxidative stress and are restricted by LRRK2 kinase activity. Collectively, these findings illustrate a dichotomous role for LRRK2 within different immune cell populations and give insight into the fundamental differences between immune regulation in the CNS and the periphery.
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Affiliation(s)
- Chi G Weindel
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Texas A&M School of Medicine, TX, 77807, USA
| | - Lily M Ellzey
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Texas A&M School of Medicine, TX, 77807, USA
| | - Aja K Coleman
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Texas A&M School of Medicine, TX, 77807, USA
| | - Kristin L Patrick
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Texas A&M School of Medicine, TX, 77807, USA
| | - Robert O Watson
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Texas A&M School of Medicine, TX, 77807, USA
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31
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Guerrero-Carrasco M, Targett I, Olmos-Alonso A, Vargas-Caballero M, Gomez-Nicola D. Low-grade systemic inflammation stimulates microglial turnover and accelerates the onset of Alzheimer's-like pathology. Glia 2024; 72:1340-1355. [PMID: 38597386 DOI: 10.1002/glia.24532] [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: 12/07/2023] [Revised: 03/22/2024] [Accepted: 03/26/2024] [Indexed: 04/11/2024]
Abstract
Several in vivo studies have shown that systemic inflammation, mimicked by LPS, triggers an inflammatory response in the CNS, driven by microglia, characterized by an increase in inflammatory cytokines and associated sickness behavior. However, most studies induce relatively high systemic inflammation, not directly compared with the more common low-grade inflammatory events experienced in humans during the life course. Using mice, we investigated the effects of low-grade systemic inflammation during an otherwise healthy early life, and how this may precondition the onset and severity of Alzheimer's disease (AD)-like pathology. Our results indicate that low-grade systemic inflammation induces sub-threshold brain inflammation and promotes microglial proliferation driven by the CSF1R pathway, contrary to the effects caused by high systemic inflammation. In addition, repeated systemic challenges with low-grade LPS induce disease-associated microglia. Finally, using an inducible model of AD-like pathology (Line 102 mice), we observed that preconditioning with repeated doses of low-grade systemic inflammation, prior to APP induction, promotes a detrimental effect later in life, leading to an increase in Aβ accumulation and disease-associated microglia. These results support the notion that episodic low-grade systemic inflammation has the potential to influence the onset and severity of age-related neurological disorders, such as AD.
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Affiliation(s)
- Monica Guerrero-Carrasco
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Imogen Targett
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Adrian Olmos-Alonso
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Mariana Vargas-Caballero
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
- Institute for Life Sciences (IfLS), University of Southampton, Southampton, UK
| | - Diego Gomez-Nicola
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
- Institute for Life Sciences (IfLS), University of Southampton, Southampton, UK
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32
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Li G, Wang Y, Qian L, Li D, Yao Y, Pan J, Fan D. C8-ceramide modulates microglia BDNF expression to alleviate postoperative cognition dysfunction via PKCδ/NF-κB signaling pathway. Exp Brain Res 2024; 242:1543-1559. [PMID: 38750371 PMCID: PMC11208206 DOI: 10.1007/s00221-024-06847-2] [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: 12/07/2023] [Accepted: 05/06/2024] [Indexed: 06/27/2024]
Abstract
Postoperative cognitive dysfunction (POCD) is a kind of serious postoperative complication in surgery with general anesthesia and it may affect patients' normal lives. Activated microglia are thought to be one of the key factors in the regulation of POCD process. Once activated, resident microglia change their phenotype and secrete kinds of cytokines to regulate inflammatory response in tissues. Among these secretory factors, brain-derived neurotrophic factor (BDNF) is considered to be able to inhibit inflammation response and protect nervous system. Therefore, the enhancement of BDNF expression derived from resident microglia is suggested to be potential treatment for POCD. In our study, we focused on the role of C8-ceramide (a kind of interventional drug) and assessed its regulatory effect on improving the expression of BDNF secreted from microglia to treat POCD. According to the results of our study, we observed that C8-ceramide stimulated primary microglia to up-regulate the expression of BDNF mRNA after being treated with lipopolysaccharide (LPS) in vitro. We proved that C8-ceramide had ability to effectively improve POCD of mice after being accepted carotid artery exposure and their abnormal behavior recovered better than that of mice from the surgery group. Furthermore, we also demonstrated that C8-ceramide enhanced the cognitive function of mice via the PKCδ/NF-κB signaling pathway. In general, our study has confirmed a potential molecular mechanism that led to the occurrence of POCD caused by surgery and provided a new clinical strategy to treat POCD.
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Affiliation(s)
- Guangqian Li
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, #32 West Second Section, First-Ring Road, Chengdu, 610072, People's Republic of China
| | - Yuhao Wang
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
- Frontier Innovation Center for Dental Medicine Plus, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Lei Qian
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, #32 West Second Section, First-Ring Road, Chengdu, 610072, People's Republic of China
| | - Danni Li
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, #32 West Second Section, First-Ring Road, Chengdu, 610072, People's Republic of China
| | - Yuchen Yao
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, #32 West Second Section, First-Ring Road, Chengdu, 610072, People's Republic of China
| | - Jian Pan
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
- Frontier Innovation Center for Dental Medicine Plus, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Dan Fan
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, #32 West Second Section, First-Ring Road, Chengdu, 610072, People's Republic of China.
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Przepiórska-Drońska K, Wnuk A, Pietrzak-Wawrzyńska BA, Łach A, Biernat W, Wójtowicz AK, Kajta M. Amorfrutin B Compromises Hypoxia/Ischemia-induced Activation of Human Microglia in a PPARγ-dependent Manner: Effects on Inflammation, Proliferation Potential, and Mitochondrial Status. J Neuroimmune Pharmacol 2024; 19:34. [PMID: 38949694 PMCID: PMC11217078 DOI: 10.1007/s11481-024-10135-9] [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: 12/22/2023] [Accepted: 06/08/2024] [Indexed: 07/02/2024]
Abstract
Amorfrutin B is a selective PPARγ modulator that we demonstrated to be a promising neuroprotective compound in cellular models of stroke and perinatal asphyxia. Although neuronal mechanisms of amorfrutin B-evoked neuroprotection have been identified, none of them reflects the actions of the compound on microglia, which play a pivotal role in brain response to hypoxia/ischemia. Here, we provide evidence for amorfrutin B-induced effects on human microglia subjected to hypoxia/ischemia; the compound counteracts inflammation, and influences mitochondrial status and proliferation potential in a PPARγ-dependent manner. Post-treatment with amorfrutin B decreased the IBA1 fluorescence intensity, reduced caspase-1 activity, and downregulated IL1B/IL-1β and TNFA but not IL10/IL-10 expression, which was upregulated. Amorfrutin B also stimulated PPARγ signaling, as evidenced by increased mRNA and/or protein levels of PPARγ and PGC1α. In addition, amorfrutin B reversed the hypoxia/ischemia-evoked effects on mitochondria-related parameters, such as mitochondrial membrane potential, BCL2/BCL2 expression and metabolic activity, which were correlated with diminished proliferation potential of microglia. Interestingly, the inhibitory effect of amorfrutin B on the proliferation potential and mitochondrial function of microglia is opposite to the stimulatory effect of amorfrutin B on mouse neuronal survival, as evidenced by increased neuronal viability and reduced neurodegeneration. In summary, this study showed for the first time that amorfrutin B compromises hypoxia/ischemia-induced activation of human microglia in a PPARγ-dependent manner, which involves inhibiting inflammation, normalizing mitochondrial status, and controlling proliferation potential. These data extend the protective potential of amorfrutin B in the pharmacotherapy of hypoxic/ischemic brain injury, targeting not only neurons but also activated microglia.
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Affiliation(s)
- Karolina Przepiórska-Drońska
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Laboratory of Neuropharmacology and Epigenetics, Smetna Street 12, 31-343, Krakow, Poland
| | - Agnieszka Wnuk
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Laboratory of Neuropharmacology and Epigenetics, Smetna Street 12, 31-343, Krakow, Poland
| | - Bernadeta Angelika Pietrzak-Wawrzyńska
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Laboratory of Neuropharmacology and Epigenetics, Smetna Street 12, 31-343, Krakow, Poland
| | - Andrzej Łach
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Laboratory of Neuropharmacology and Epigenetics, Smetna Street 12, 31-343, Krakow, Poland
| | - Weronika Biernat
- Faculty of Animal Sciences, Department of Nutrition, Animal Biotechnology and Fisheries, University of Agriculture, Adama Mickiewicza 24/28, 30-059, Krakow, Poland
| | - Anna Katarzyna Wójtowicz
- Faculty of Animal Sciences, Department of Nutrition, Animal Biotechnology and Fisheries, University of Agriculture, Adama Mickiewicza 24/28, 30-059, Krakow, Poland
| | - Małgorzata Kajta
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Laboratory of Neuropharmacology and Epigenetics, Smetna Street 12, 31-343, Krakow, Poland.
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Baumgartner A, Robinson M, Golde T, Jaydev S, Huang S, Hadlock J, Funk C. Fokker-Planck diffusion maps of multiple single cell microglial transcriptomes reveals radial differentiation into substates associated with Alzheimer's pathology. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.21.599924. [PMID: 38979220 PMCID: PMC11230164 DOI: 10.1101/2024.06.21.599924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
The identification of microglia subtypes is important for understanding the role of innate immunity in neurodegenerative diseases. Current methods of unsupervised cell type identification assume a small noise-to-signal ratio of transcriptome measurements that would produce well-separated cell clusters. However, identification of subtypes is obscured by gene expression noise, diminishing the distances in transcriptome space between distinct cell types and blurring boundaries. Here we use Fokker-Planck (FP) diffusion maps to model cellular differentiation as a stochastic process whereby cells settle into local minima, corresponding to cell subtypes, in a potential landscape constructed from transcriptome data using a nearest neighbor graph approach. By applying critical transition fields, we identify individual cells on the verge of transitioning between subtypes, revealing microglial cells in inactivated, homeostatic state before radially transitioning into various specialized subtypes. Specifically, we show that cells from Alzheimer's disease patients are enriched in a microglia subtype associated to antigen presentation and T-cell recruitment.
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Affiliation(s)
| | | | - Todd Golde
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Institute Emory Brain Health, Emory University School of Medicine, Atlanta, GA, USA
| | - Suman Jaydev
- Department of Neurology, University of Washington, Seattle, WA, USA
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
- Division of Medical Genetics, University of Washington, Seattle, WA, USA
| | - Sui Huang
- Institute for Systems Biology, Seattle, WA
| | - Jennifer Hadlock
- Institute for Systems Biology, Seattle, WA
- Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, USA
| | - Cory Funk
- Institute for Systems Biology, Seattle, WA
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35
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Barry-Carroll L, Gomez-Nicola D. The molecular determinants of microglial developmental dynamics. Nat Rev Neurosci 2024; 25:414-427. [PMID: 38658739 DOI: 10.1038/s41583-024-00813-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2024] [Indexed: 04/26/2024]
Abstract
Microglia constitute the largest population of parenchymal macrophages in the brain and are considered a unique subset of central nervous system glial cells owing to their extra-embryonic origins in the yolk sac. During development, microglial progenitors readily proliferate and eventually colonize the entire brain. In this Review, we highlight the origins of microglial progenitors and their entry routes into the brain and discuss the various molecular and non-molecular determinants of their fate, which may inform their specific functions. Specifically, we explore recently identified mechanisms that regulate microglial colonization of the brain, including the availability of space, and describe how the expansion of highly proliferative microglial progenitors facilitates the occupation of the microglial niche. Finally, we shed light on the factors involved in establishing microglial identity in the brain.
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Affiliation(s)
- Liam Barry-Carroll
- Nutrineuro, UMR 1286 INRAE, Bordeaux University, Bordeaux INP, Bordeaux, France
| | - Diego Gomez-Nicola
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK.
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36
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Lu HJ, Guo D, Wei QQ. Potential of Neuroinflammation-Modulating Strategies in Tuberculous Meningitis: Targeting Microglia. Aging Dis 2024; 15:1255-1276. [PMID: 37196131 PMCID: PMC11081169 DOI: 10.14336/ad.2023.0311] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 03/11/2023] [Indexed: 05/19/2023] Open
Abstract
Tuberculous meningitis (TBM) is the most severe complication of tuberculosis (TB) and is associated with high rates of disability and mortality. Mycobacterium tuberculosis (M. tb), the infectious agent of TB, disseminates from the respiratory epithelium, breaks through the blood-brain barrier, and establishes a primary infection in the meninges. Microglia are the core of the immune network in the central nervous system (CNS) and interact with glial cells and neurons to fight against harmful pathogens and maintain homeostasis in the brain through pleiotropic functions. However, M. tb directly infects microglia and resides in them as the primary host for bacillus infections. Largely, microglial activation slows disease progression. The non-productive inflammatory response that initiates the secretion of pro-inflammatory cytokines and chemokines may be neurotoxic and aggravate tissue injuries based on damages caused by M. tb. Host-directed therapy (HDT) is an emerging strategy for modulating host immune responses against diverse diseases. Recent studies have shown that HDT can control neuroinflammation in TBM and act as an adjunct therapy to antibiotic treatment. In this review, we discuss the diverse roles of microglia in TBM and potential host-directed TB therapies that target microglia to treat TBM. We also discuss the limitations of applying each HDT and suggest a course of action for the near future.
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Affiliation(s)
- Huan-Jun Lu
- Institute of Special Environmental Medicine, Nantong University, Jiangsu, China
| | - Daji Guo
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qian-Qi Wei
- Department of Infectious Diseases, General Hospital of Tibet Military Command, Xizang, China
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Fancy NN, Smith AM, Caramello A, Tsartsalis S, Davey K, Muirhead RCJ, McGarry A, Jenkyns MH, Schneegans E, Chau V, Thomas M, Boulger S, Cheung TKD, Adair E, Papageorgopoulou M, Willumsen N, Khozoie C, Gomez-Nicola D, Jackson JS, Matthews PM. Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics. Acta Neuropathol 2024; 147:78. [PMID: 38695952 PMCID: PMC11065703 DOI: 10.1007/s00401-024-02727-9] [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: 01/04/2024] [Revised: 03/11/2024] [Accepted: 03/28/2024] [Indexed: 05/05/2024]
Abstract
Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer's disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.
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Affiliation(s)
- Nurun N Fancy
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Amy M Smith
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- Centre for Brain Research and Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Alessia Caramello
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Stergios Tsartsalis
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- Department of Psychiatry, University of Geneva, Geneva, Switzerland
| | - Karen Davey
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
- UK Dementia Research Institute Centre, King's College London, London, UK
| | - Robert C J Muirhead
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
- UK Dementia Research Institute Centre, King's College London, London, UK
| | - Aisling McGarry
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Marion H Jenkyns
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Eleonore Schneegans
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Vicky Chau
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Michael Thomas
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Sam Boulger
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - To Ka Dorcas Cheung
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Emily Adair
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Marianna Papageorgopoulou
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Nanet Willumsen
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Combiz Khozoie
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Diego Gomez-Nicola
- School of Biological Sciences, University of Southampton, Southampton, UK
| | - Johanna S Jackson
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- UK Dementia Research Institute Centre, Imperial College London, London, UK
| | - Paul M Matthews
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
- UK Dementia Research Institute Centre, Imperial College London, London, UK.
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Ayyubova G, Fazal N. Beneficial versus Detrimental Effects of Complement-Microglial Interactions in Alzheimer's Disease. Brain Sci 2024; 14:434. [PMID: 38790413 PMCID: PMC11119363 DOI: 10.3390/brainsci14050434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/26/2024] Open
Abstract
Research indicates that brain-region-specific synapse loss and dysfunction are early hallmarks and stronger neurobiological correlates of cognitive decline in Alzheimer's disease (AD) than amyloid plaque and neurofibrillary tangle counts or neuronal loss. Even though the precise mechanisms underlying increased synaptic pruning in AD are still unknown, it has been confirmed that dysregulation of the balance between complement activation and inhibition is a crucial driver of its pathology. The complement includes three distinct activation mechanisms, with the activation products C3a and C5a, potent inflammatory effectors, and a membrane attack complex (MAC) leading to cell lysis. Besides pro-inflammatory cytokines, the dysregulated complement proteins released by activated microglia bind to amyloid β at the synaptic regions and cause the microglia to engulf the synapses. Additionally, research indicating that microglia-removed synapses are not always degenerating and that suppression of synaptic engulfment can repair cognitive deficits points to an essential opportunity for intervention that can prevent the loss of intact synapses. In this study, we focus on the latest research on the role and mechanisms of complement-mediated microglial synaptic pruning at different stages of AD to find the right targets that could interfere with complement dysregulation and be relevant for therapeutic intervention at the early stages of the disease.
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Affiliation(s)
- Gunel Ayyubova
- Department of Cytology, Embryology and Histology, Azerbaijan Medical University, Baku 370022, Azerbaijan;
| | - Nadeem Fazal
- College of Health Sciences and Pharmacy, Chicago State University, Chicago, IL 60628, USA
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Leal-Nazaré CG, Arrifano GP, Lopes-Araújo A, Santos-Sacramento L, Barthelemy JL, Soares-Silva I, Crespo-Lopez ME, Augusto-Oliveira M. Methylmercury neurotoxicity: Beyond the neurocentric view. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 920:170939. [PMID: 38365040 DOI: 10.1016/j.scitotenv.2024.170939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/09/2024] [Accepted: 02/10/2024] [Indexed: 02/18/2024]
Abstract
Mercury is a highly toxic metal widely used in human activities worldwide, therefore considered a global public health problem. Many cases of mercury intoxication have occurred in history and represent a huge challenge nowadays. Of particular importance is its methylated form, methylmercury (MeHg). This mercurial species induces damage to several organs in the human body, especially to the central nervous system. Neurological impairments such as executive, memory, motor and visual deficits are associated with MeHg neurotoxicity. Molecular mechanisms involved in MeHg-induced neurotoxicity include excitotoxicity due to glutamatergic imbalance, disturbance in calcium homeostasis and oxidative balance, failure in synaptic support, and inflammatory response. Although neurons are largely affected by MeHg intoxication, they only represent half of the brain cells. Glial cells represent roughly 50 % of the brain cells and are key elements in the functioning of the central nervous system. Particularly, astrocytes and microglia are deeply involved in MeHg-induced neurotoxicity, resulting in distinct neurological outcomes depending on the context. In this review, we discuss the main findings on astroglial and microglial involvement as mediators of neuroprotective and neurotoxic responses to MeHg intoxication. The literature shows that these responses depend on chemical and morphophysiological features, thus, we present some insights for future investigations, considering the particularities of the context, including time and dose of exposure, brain region, and species of study.
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Affiliation(s)
- Caio Gustavo Leal-Nazaré
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | - Gabriela P Arrifano
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | - Amanda Lopes-Araújo
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | - Leticia Santos-Sacramento
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | - Jean Ludger Barthelemy
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | - Isabela Soares-Silva
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | - Maria Elena Crespo-Lopez
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil.
| | - Marcus Augusto-Oliveira
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil.
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Macé L, Brizais C, Bachelot F, Manoury A, Thomé S, Gloaguen C, Garali I, Magneron V, Monceau V, Sache A, Voyer F, Elie C, Roy L, Gensdarmes F, Klokov D, Block ML, Ibanez C. Exposure to tungsten particles via inhalation triggers early toxicity marker expression in the rat brain. Inhal Toxicol 2024; 36:261-274. [PMID: 38836331 DOI: 10.1080/08958378.2024.2349895] [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: 10/03/2023] [Accepted: 04/26/2024] [Indexed: 06/06/2024]
Abstract
OBJECTIVE Our work is focused on tungsten, considered as an emerging contaminant. Its environmental dispersion is partly due to mining and military activities. Exposure scenario can also be occupational, in areas such as the hard metal industry and specific nuclear facilities. Our study investigated the cerebral effects induced by the inhalation of tungsten particles. METHODS Inhalation exposure campaigns were carried out at two different concentrations (5 and 80 mg/m3) in single and repeated modes (4 consecutive days) in adult rats within a nose-only inhalation chamber. Processes involved in brain toxicity were investigated 24 h after exposure. RESULTS AND DISCUSSION Site-specific effects in terms of neuroanatomy and concentration-dependent changes in specific cellular actors were observed. Results obtained in the olfactory bulb suggest a potential early effect on the survival of microglial cells. Depending on the mode of exposure, these cells showed a decrease in density accompanied by an increase in an apoptotic marker. An abnormal phenotype of the nuclei of mature neurons, suggesting neuronal suffering, was also observed in the frontal cortex, and can be linked to the involvement of oxidative stress. The differential effects observed according to exposure patterns could involve two components: local (brain-specific) and/or systemic. Indeed, tungsten, in addition to being found in the lungs and kidneys, was present in the brain of animals exposed to the high concentration. CONCLUSION Our data question the perceived innocuity of tungsten relative to other metals and raise hypotheses regarding possible adaptive or neurotoxic mechanisms that could ultimately alter neuronal integrity.
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Affiliation(s)
- Léo Macé
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Chloé Brizais
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Florence Bachelot
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Annabelle Manoury
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Sébastien Thomé
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Céline Gloaguen
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Imène Garali
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Victor Magneron
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Virginie Monceau
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Amandine Sache
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Frédéric Voyer
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Christelle Elie
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - Laurence Roy
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
| | - François Gensdarmes
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Sûreté Nucléaire, Service du Confinement et de l'Aérodispersion des Polluants, Gif-sur-YvetteCedex, France
| | - Dmitry Klokov
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada
| | - Michelle L Block
- Department of Pharmacology and Toxicology, The Stark Neurosciences Research Institute, IN University School of Medicine, Indianapolis, IN, USA
| | - Chrystelle Ibanez
- Institut de Radioprotection et de Sûreté Nucléaire, Pôle Santé Environnement, Service de recherche sur les effets biologiques et sanitaires des rayonnements ionisants, Avenue de la Division Leclerc, Fontenay aux Roses, France
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Zhang Y, Li J, Zhao Y, Huang Y, Shi Z, Wang H, Cao H, Wang C, Wang Y, Chen D, Chen S, Meng S, Wang Y, Zhu Y, Jiang Y, Gong Y, Gao Y. Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke. SCIENCE ADVANCES 2024; 10:eade6900. [PMID: 38446877 PMCID: PMC10917353 DOI: 10.1126/sciadv.ade6900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/30/2024] [Indexed: 03/08/2024]
Abstract
The accumulation of self-renewed polarized microglia in the penumbra is a critical neuroinflammatory process after ischemic stroke, leading to secondary demyelination and neuronal loss. Although known to regulate tumor cell proliferation and neuroinflammation, HDAC3's role in microgliosis and microglial polarization remains unclear. We demonstrated that microglial HDAC3 knockout (HDAC3-miKO) ameliorated poststroke long-term functional and histological outcomes. RNA-seq analysis revealed mitosis as the primary process affected in HDAC3-deficent microglia following stroke. Notably, HDAC3-miKO specifically inhibited proliferation of proinflammatory microglia without affecting anti-inflammatory microglia, preventing microglial transition to a proinflammatory state. Moreover, ATAC-seq showed that HDAC3-miKO induced closing of accessible regions enriched with PU.1 motifs. Overexpressing microglial PU.1 via an AAV approach reversed HDAC3-miKO-induced proliferation inhibition and protective effects on ischemic stroke, indicating PU.1 as a downstream molecule that mediates HDAC3's effects on stroke. These findings uncovered that HDAC3/PU.1 axis, which mediated differential proliferation-related reprogramming in different microglia populations, drove poststroke inflammatory state transition, and contributed to pathophysiology of ischemic stroke.
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Affiliation(s)
| | | | | | - Yichen Huang
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Ziyu Shi
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Hailian Wang
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Hui Cao
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Chenran Wang
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yana Wang
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Di Chen
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Shuning Chen
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Shan Meng
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yangfan Wang
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yueyan Zhu
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yan Jiang
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Ye Gong
- Corresponding author. (Y.Gao); (Y.Gong)
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Rao Y, Peng B. Allogenic microglia replacement: A novel therapeutic strategy for neurological disorders. FUNDAMENTAL RESEARCH 2024; 4:237-245. [PMID: 38933508 PMCID: PMC11197774 DOI: 10.1016/j.fmre.2023.02.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 11/17/2022] [Accepted: 02/19/2023] [Indexed: 03/29/2023] Open
Abstract
Microglia are resident immune cells in the central nervous system (CNS) that play vital roles in CNS development, homeostasis and disease pathogenesis. Genetic defects in microglia lead to microglial dysfunction, which in turn leads to neurological disorders. The correction of the specific genetic defects in microglia in these disorders can lead to therapeutic effects. Traditional genetic defect correction approaches are dependent on viral vector-based genetic defect corrections. However, the viruses used in these approaches, including adeno-associated viruses, lentiviruses and retroviruses, do not primarily target microglia; therefore, viral vector-based genetic defect corrections are ineffective in microglia. Microglia replacement is a novel approach to correct microglial genetic defects via replacing microglia of genetic defects with allogenic healthy microglia. In this paper, we systematically review the history, rationale and therapeutic perspectives of microglia replacement, which would be a novel strategy for treating CNS disorders.
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Affiliation(s)
- Yanxia Rao
- Department of Laboratory Animal Science, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China
| | - Bo Peng
- Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai 200000, China
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China
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Van Steenwinckel J, Bokobza C, Laforge M, Shearer IK, Miron VE, Rua R, Matta SM, Hill‐Yardin EL, Fleiss B, Gressens P. Key roles of glial cells in the encephalopathy of prematurity. Glia 2024; 72:475-503. [PMID: 37909340 PMCID: PMC10952406 DOI: 10.1002/glia.24474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/17/2023] [Accepted: 09/19/2023] [Indexed: 11/03/2023]
Abstract
Across the globe, approximately one in 10 babies are born preterm, that is, before 37 weeks of a typical 40 weeks of gestation. Up to 50% of preterm born infants develop brain injury, encephalopathy of prematurity (EoP), that substantially increases their risk for developing lifelong defects in motor skills and domains of learning, memory, emotional regulation, and cognition. We are still severely limited in our abilities to prevent or predict preterm birth. No longer just the "support cells," we now clearly understand that during development glia are key for building a healthy brain. Glial dysfunction is a hallmark of EoP, notably, microgliosis, astrogliosis, and oligodendrocyte injury. Our knowledge of glial biology during development is exponentially expanding but hasn't developed sufficiently for development of effective neuroregenerative therapies. This review summarizes the current state of knowledge for the roles of glia in infants with EoP and its animal models, and a description of known glial-cell interactions in the context of EoP, such as the roles for border-associated macrophages. The field of perinatal medicine is relatively small but has worked passionately to improve our understanding of the etiology of EoP coupled with detailed mechanistic studies of pre-clinical and human cohorts. A primary finding from this review is that expanding our collaborations with computational biologists, working together to understand the complexity of glial subtypes, glial maturation, and the impacts of EoP in the short and long term will be key to the design of therapies that improve outcomes.
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Affiliation(s)
| | - Cindy Bokobza
- NeuroDiderot, INSERMUniversité Paris CitéParisFrance
| | | | - Isabelle K. Shearer
- School of Health and Biomedical SciencesSTEM College, RMIT UniversityBundooraVictoriaAustralia
| | - Veronique E. Miron
- Barlo Multiple Sclerosis CentreSt. Michael's HospitalTorontoOntarioCanada
- Department of ImmunologyUniversity of TorontoTorontoOntarioCanada
- College of Medicine and Veterinary MedicineThe Dementia Research Institute at The University of EdinburghEdinburghUK
| | - Rejane Rua
- CNRS, INSERM, Centre d'Immunologie de Marseille‐Luminy (CIML), Turing Centre for Living SystemsAix‐Marseille UniversityMarseilleFrance
| | - Samantha M. Matta
- School of Health and Biomedical SciencesSTEM College, RMIT UniversityBundooraVictoriaAustralia
| | - Elisa L. Hill‐Yardin
- School of Health and Biomedical SciencesSTEM College, RMIT UniversityBundooraVictoriaAustralia
| | - Bobbi Fleiss
- NeuroDiderot, INSERMUniversité Paris CitéParisFrance
- School of Health and Biomedical SciencesSTEM College, RMIT UniversityBundooraVictoriaAustralia
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Weathered C, Bardehle S, Yoon C, Kumar N, Leyns CEG, Kennedy ME, Bloomingdale P, Pienaar E. Microglial roles in Alzheimer's disease: An agent-based model to elucidate microglial spatiotemporal response to beta-amyloid. CPT Pharmacometrics Syst Pharmacol 2024; 13:449-463. [PMID: 38078626 PMCID: PMC10941569 DOI: 10.1002/psp4.13095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 11/16/2023] [Accepted: 11/20/2023] [Indexed: 02/03/2024] Open
Abstract
Alzheimer's disease (AD) is characterized by beta-amyloid (Aβ) plaques in the brain and widespread neuronal damage. Because of the high drug attrition rates in AD, there is increased interest in characterizing neuroimmune responses to Aβ plaques. In response to AD pathology, microglia are innate phagocytotic immune cells that transition into a neuroprotective state and form barriers around plaques. We seek to understand the role of microglia in modifying Aβ dynamics and barrier formation. To quantify the influence of individual microglia behaviors (activation, chemotaxis, phagocytosis, and proliferation) on plaque size and barrier coverage, we developed an agent-based model to characterize the spatiotemporal interactions between microglia and Aβ. Our model qualitatively reproduces mouse data trends where the fraction of microglia coverage decreases as plaques become larger. In our model, the time to microglial arrival at the plaque boundary is significantly negatively correlated (p < 0.0001) with plaque size, indicating the importance of the time to microglial activation for regulating plaque size. In addition, in silico behavioral knockout simulations show that phagocytosis knockouts have the strongest impact on plaque size, but modest impacts on microglial coverage and activation. In contrast, the chemotaxis knockouts had a strong impact on microglial coverage with a more modest impact on plaque volume and microglial activation. These simulations suggest that phagocytosis, chemotaxis, and replication of activated microglia have complex impacts on plaque volume and coverage, whereas microglial activation remains fairly robust to perturbations of these functions. Thus, our work provides insights into the potential and limitations of targeting microglial activation as a pharmacological strategy for the treatment of AD.
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Affiliation(s)
- Catherine Weathered
- Weldon School of Biomedical EngineeringPurdue UniversityWest LafayetteIndianaUSA
| | - Sophia Bardehle
- NeuroimmunologyMerck & Co., Inc.RahwayNew JerseyUSA
- Present address:
Cerevel TherapeuticsCambridgeMassachusettsUSA
| | - Choya Yoon
- NeuroimmunologyMerck & Co., Inc.RahwayNew JerseyUSA
| | - Niyanta Kumar
- Pharmacokinetics and PharmacodynamicsMerck & Co., Inc.RahwayNew JerseyUSA
- Present address:
Mersana TherapeuticsCambridgeMassachusettsUSA
| | | | | | - Peter Bloomingdale
- Quantitative Pharmacology and PharmacometricsMerck & Co., Inc.RahwayNew JerseyUSA
- Present address:
Boehringer IngelheimIngelheim am RheinGermany
| | - Elsje Pienaar
- Weldon School of Biomedical EngineeringPurdue UniversityWest LafayetteIndianaUSA
- Regenstrief Center for Healthcare EngineeringWest LafayetteIndianaUSA
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Laaksonen S, Saraste M, Nylund M, Hinz R, Snellman A, Rinne J, Matilainen M, Airas L. Sex-driven variability in TSPO-expressing microglia in MS patients and healthy individuals. Front Neurol 2024; 15:1352116. [PMID: 38445263 PMCID: PMC10913932 DOI: 10.3389/fneur.2024.1352116] [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: 12/07/2023] [Accepted: 01/31/2024] [Indexed: 03/07/2024] Open
Abstract
Background Males with multiple sclerosis (MS) have a higher risk for disability progression than females, but the reasons for this are unclear. Objective We hypothesized that potential differences in TSPO-expressing microglia between female and male MS patients could contribute to sex differences in clinical disease progression. Methods The study cohort consisted of 102 MS patients (mean (SD) age 45.3 (9.7) years, median (IQR) disease duration 12.1 (7.0-17.2) years, 72% females, 74% relapsing-remitting MS) and 76 age- and sex-matched healthy controls. TSPO-expressing microglia were measured using the TSPO-binding radioligand [11C](R)-PK11195 and brain positron emission tomography (PET). TSPO-binding was quantified as distribution volume ratio (DVR) in normal-appearing white matter (NAWM), thalamus, whole brain and cortical gray matter (cGM). Results Male MS patients had higher DVRs compared to female patients in the whole brain [1.22 (0.04) vs. 1.20 (0.02), p = 0.002], NAWM [1.24 (0.06) vs. 1.21 (0.05), p = 0.006], thalamus [1.37 (0.08) vs. 1.32 (0.02), p = 0.008] and cGM [1.25 (0.04) vs. 1.23 (0.04), p = 0.028]. Similarly, healthy men had higher DVRs compared to healthy women except for cGM. Of the studied subgroups, secondary progressive male MS patients had the highest DVRs in all regions, while female controls had the lowest DVRs. Conclusion We observed higher TSPO-binding in males compared to females among people with MS and in healthy individuals. This sex-driven inherent variability in TSPO-expressing microglia may predispose male MS patients to greater likelihood of disease progression.
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Affiliation(s)
- Sini Laaksonen
- Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland
- Neurocenter, Turku University Hospital, Turku, Finland
- Clinical Neurosciences, University of Turku, Turku, Finland
| | - Maija Saraste
- Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland
- Clinical Neurosciences, University of Turku, Turku, Finland
| | - Marjo Nylund
- Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland
- Neurocenter, Turku University Hospital, Turku, Finland
- Clinical Neurosciences, University of Turku, Turku, Finland
- InFLAMES Research Flagship, University of Turku, Turku, Finland
| | - Rainer Hinz
- Wolfson Molecular Imaging Centre, University of Manchester, Manchester, United Kingdom
| | - Anniina Snellman
- Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland
- Clinical Neurosciences, University of Turku, Turku, Finland
| | - Juha Rinne
- Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland
- Neurocenter, Turku University Hospital, Turku, Finland
- Clinical Neurosciences, University of Turku, Turku, Finland
- InFLAMES Research Flagship, University of Turku, Turku, Finland
| | - Markus Matilainen
- Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland
- Clinical Neurosciences, University of Turku, Turku, Finland
| | - Laura Airas
- Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland
- Neurocenter, Turku University Hospital, Turku, Finland
- Clinical Neurosciences, University of Turku, Turku, Finland
- InFLAMES Research Flagship, University of Turku, Turku, Finland
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46
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Bobotis BC, Halvorson T, Carrier M, Tremblay MÈ. Established and emerging techniques for the study of microglia: visualization, depletion, and fate mapping. Front Cell Neurosci 2024; 18:1317125. [PMID: 38425429 PMCID: PMC10902073 DOI: 10.3389/fncel.2024.1317125] [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: 10/10/2023] [Accepted: 01/15/2024] [Indexed: 03/02/2024] Open
Abstract
The central nervous system (CNS) is an essential hub for neuronal communication. As a major component of the CNS, glial cells are vital in the maintenance and regulation of neuronal network dynamics. Research on microglia, the resident innate immune cells of the CNS, has advanced considerably in recent years, and our understanding of their diverse functions continues to grow. Microglia play critical roles in the formation and regulation of neuronal synapses, myelination, responses to injury, neurogenesis, inflammation, and many other physiological processes. In parallel with advances in microglial biology, cutting-edge techniques for the characterization of microglial properties have emerged with increasing depth and precision. Labeling tools and reporter models are important for the study of microglial morphology, ultrastructure, and dynamics, but also for microglial isolation, which is required to glean key phenotypic information through single-cell transcriptomics and other emerging approaches. Strategies for selective microglial depletion and modulation can provide novel insights into microglia-targeted treatment strategies in models of neuropsychiatric and neurodegenerative conditions, cancer, and autoimmunity. Finally, fate mapping has emerged as an important tool to answer fundamental questions about microglial biology, including their origin, migration, and proliferation throughout the lifetime of an organism. This review aims to provide a comprehensive discussion of these established and emerging techniques, with applications to the study of microglia in development, homeostasis, and CNS pathologies.
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Affiliation(s)
- Bianca Caroline Bobotis
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology, Victoria, BC, Canada
| | - Torin Halvorson
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- Department of Surgery, University of British Columbia, Vancouver, BC, Canada
- British Columbia Children’s Hospital Research Institute, Vancouver, BC, Canada
| | - Micaël Carrier
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Département de Psychiatrie et de Neurosciences, Faculté de Médecine, Université Laval, Québec City, QC, Canada
- Axe neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
| | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology, Victoria, BC, Canada
- Axe neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
- Department of Molecular Medicine, Université Laval, Québec City, QC, Canada
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47
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Jiang G, Hong J, Sun L, Wei H, Gong W, Wang S, Zhu J. Glycolysis regulation in tumor-associated macrophages: Its role in tumor development and cancer treatment. Int J Cancer 2024; 154:412-424. [PMID: 37688376 DOI: 10.1002/ijc.34711] [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: 04/18/2023] [Revised: 07/27/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023]
Abstract
Tumor-associated macrophages constitute the main cell population in the tumor microenvironment and play a crucial role in regulating the microenvironment composition. Emerging evidence has revealed that the metabolic profile determines the tumor-associated macrophage phenotype. Tumor-associated macrophage function is highly dependent on glucose metabolism, with glycolysis being the major metabolic pathway. Recent reports have demonstrated diversity in glucose flux of tumor-associated macrophages and complex substance communication with cancer cells. However, how the glucose flux in tumor-associated macrophages connects with glycolysis to influence tumor progression and the tumor microenvironment is still obscure. Moreover, while the development of single-cell sequencing technology allows a clearer and more accurate classification of tumor-associated macrophages, the metabolic profiles of tumor-associated macrophages from the perspective of single-cell omics has not been well summarized. Here, we review the current state of knowledge on glucose metabolism in tumor-associated macrophages and summarize the metabolic profiles of different tumor-associated macrophage subtypes from the perspective of single-cell omics. Additionally, we describe the current strategies targeting glycolysis in tumor-associated macrophages for cancer therapy.
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Affiliation(s)
- Guangyi Jiang
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Junjie Hong
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Lu Sun
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Haibin Wei
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Wangang Gong
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Shu Wang
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Jianqing Zhu
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
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Askew KE, Beverley J, Sigfridsson E, Szymkowiak S, Emelianova K, Dando O, Hardingham GE, Duncombe J, Hennessy E, Koudelka J, Samarasekera N, Salman RA, Smith C, Tavares AAS, Gomez‐Nicola D, Kalaria RN, McColl BW, Horsburgh K. Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment. Glia 2024; 72:375-395. [PMID: 37909242 PMCID: PMC10952452 DOI: 10.1002/glia.24481] [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: 06/02/2023] [Revised: 09/27/2023] [Accepted: 10/04/2023] [Indexed: 11/02/2023]
Abstract
White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.
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Affiliation(s)
| | - Joshua Beverley
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
| | - Emma Sigfridsson
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
| | - Stefan Szymkowiak
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Katherine Emelianova
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Owen Dando
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Giles E. Hardingham
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Jessica Duncombe
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
| | - Edel Hennessy
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
| | - Juraj Koudelka
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Neshika Samarasekera
- Centre for Clinical Brain Sciences and Sudden Death Brain BankUniversity of EdinburghEdinburghUK
| | - Rustam Al‐Shahi Salman
- Centre for Clinical Brain Sciences and Sudden Death Brain BankUniversity of EdinburghEdinburghUK
| | - Colin Smith
- Centre for Clinical Brain Sciences and Sudden Death Brain BankUniversity of EdinburghEdinburghUK
| | - Adriana A. S. Tavares
- British Heart Foundation Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | | | - Raj N. Kalaria
- Clinical and Translational Research InstituteNewcastle UniversityNewcastleUK
| | - Barry W. McColl
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Karen Horsburgh
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
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Cooper O, Hallett P, Isacson O. Upstream lipid and metabolic systems are potential causes of Alzheimer's disease, Parkinson's disease and dementias. FEBS J 2024; 291:632-645. [PMID: 36165619 PMCID: PMC10040476 DOI: 10.1111/febs.16638] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/02/2022] [Accepted: 09/26/2022] [Indexed: 11/28/2022]
Abstract
Brain health requires circuits, cells and molecular pathways to adapt when challenged and to promptly reset once the challenge has resolved. Neurodegeneration occurs when adaptability becomes confined, causing challenges to overwhelm neural circuitry. Studies of rare and common neurodegenerative diseases suggest that the accumulation of lipids can compromise circuit adaptability. Using microglia as an example, we review data that suggest increased lipid concentrations cause dysfunctional inflammatory responses to immune challenges, leading to Alzheimer's disease, Parkinson's disease and dementia. We highlight current approaches to treat lipid metabolic and clearance pathways and identify knowledge gaps towards restoring adaptive homeostasis in individuals who are at-risk of losing cognition.
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Affiliation(s)
- Oliver Cooper
- Neuroregeneration Research Institute, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478
| | - Penny Hallett
- Neuroregeneration Research Institute, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478
| | - Ole Isacson
- Neuroregeneration Research Institute, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478
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50
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Ma Q, Chen J, Kong X, Zeng Y, Chen Z, Liu H, Liu L, Lu S, Wang X. Interactions between CNS and immune cells in tuberculous meningitis. Front Immunol 2024; 15:1326859. [PMID: 38361935 PMCID: PMC10867975 DOI: 10.3389/fimmu.2024.1326859] [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: 10/24/2023] [Accepted: 01/10/2024] [Indexed: 02/17/2024] Open
Abstract
The central nervous system (CNS) harbors its own special immune system composed of microglia in the parenchyma, CNS-associated macrophages (CAMs), dendritic cells, monocytes, and the barrier systems within the brain. Recently, advances in the immune cells in the CNS provided new insights to understand the development of tuberculous meningitis (TBM), which is the predominant form of Mycobacterium tuberculosis (M.tb) infection in the CNS and accompanied with high mortality and disability. The development of the CNS requires the protection of immune cells, including macrophages and microglia, during embryogenesis to ensure the accurate development of the CNS and immune response following pathogenic invasion. In this review, we summarize the current understanding on the CNS immune cells during the initiation and development of the TBM. We also explore the interactions of immune cells with the CNS in TBM. In the future, the combination of modern techniques should be applied to explore the role of immune cells of CNS in TBM.
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Affiliation(s)
| | | | | | | | | | | | | | - Shuihua Lu
- National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, Guangdong, China
| | - Xiaomin Wang
- National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, Guangdong, China
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