Manon Blain

Montreal Neurological Institute and Hospital

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Jack P. Antel

Montreal Neurological Institute and Hospital

Alexandre Prat

Université de Montréal

Francisco J. Quintana

Broad Institute

Luke M. Healy

Montreal Neurological Institute and Hospital

Veit Rothhammer

Universitätsklinikum Erlangen

Chun‐Cheih Chao

Brigham and Women's Hospital

Stéphanie Zandee

Centre Hospitalier de l’Université de Montréal

Timothy E. Kennedy

Montreal Neurological Institute and Hospital

Moein Yaqubi

McGill University

Qiao‐Ling Cui

Montreal Neurological Institute and Hospital

Cooperative Institutions

McGill University

Harvard University

Montreal Neurological Institute and Hospital

Brigham and Women's Hospital

Université de Montréal

Karolinska Institutet

Universidad de Sevilla

Broad Institute

McGill University Health Centre

Instituto de Biomedicina de Sevilla

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Expression of a homologue of rat NG2 on human microglia

Glia (1999)

Sandrine Pouly Burkhard Becher Manon Blain Jack P. Antel

The expression of NG2 chondroitin sulfate has been widely associated with oligodendrocyte precursors in rodents. We used a monoclonal antibody (9.2.27) against the human homologue of the rat NG2 to determine whether expression of this molecule was associated with a specific glial cell population present in dissociated cell preparations derived from adult and fetal human brain tissue. Our data, derived using FACS and immunocytochemical analyses of immediately ex vivo or cultured glial cells, indicate that the large majority of NG2 expressing cells belonged to the microglial lineage (CD68, CD11c) rather than to the oligodendrocyte lineage (O4, A2B5, GalC). In situ immunohistochemistry performed on non-fixed normal spinal cord tissue confirmed the observation that NG2 is expressed by mononuclear phagocytes of the CNS. In contrast, peripheral blood-derived monocytes were NG2−. Cells from fetal brain tissue showed only small numbers of NG2+ cells, which was consistent with the number of microglial cells in this preparation. In absence of additional markers, we cannot exclude that this anti-NG2 mAb might also recognize human oligodendrocyte progenitor cells. GLIA 27:259–268, 1999. © 1999 Wiley-Liss, Inc.

Lineage markers

Neuroglia

10.1002/(sici)1098-1136(199909)27:3<259::aid-glia7>3.0.co;2-8

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Citations (57)

Microglial control of astrocytes in response to microbial metabolites

Nature (2018)

Veit Rothhammer Davis Borucki Emily Tjon Maisa C. Takenaka Chun‐Cheih Chao

Neuroglia

10.1038/s41586-018-0119-x

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Citations (831)

Microglia

Methods in molecular biology (2013)

Bertrand Joseph José L. Venero Ashley S. Harms Malú G. Tansey Amy Smith

10.1007/978-1-62703-520-0

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Citations (2)

Interferon Beta Promotes Nerve Growth Factor Secretion Early in the Course of Multiple Sclerosis

Archives of Neurology (2005)

Katarzyna Biernacki Jack P. Antel Manon Blain Sridar Narayanan Douglas L. Arnold

Interferon beta therapy has been shown to reduce the rate of clinical relapse and the frequency of magnetic resonance imaging-defined T2- weighted lesions in patients with multiple sclerosis (MS). When given early, interferon beta also reduces the rate of development of brain atrophy and improves axonal integrity. Nerve growth factor (NGF) can retard the severity and course of experimental allergic encephalomyelitis.To determine whether interferon beta effects on patients with MS could be related to modulation of neurotrophin production within the central nervous system.We studied neurotrophin production by human glial and brain endothelial cells in response to coculture with MS patient-derived lymphocytes, and correlated levels of NGF secretion with clinical and magnetic resonance imaging-defined markers of disease.We demonstrate that production of NGF by human brain microvascular endothelial cells is triggered by interaction with T lymphocytes derived from MS patients. No such response was observed using human adult microglia or human fetal astrocytes. Nerve growth factor production by endothelial cells was potentiated by pretreating lymphocytes with interferon beta in vitro, and by using lymphocytes derived from MS patients treated with interferon beta in vivo. By using this assay, we show that levels of NGF induced by lymphocytes from MS patients inversely correlate with magnetic resonance imaging measures of brain atrophy and axonal injury.These findings suggest that interferon beta-mediated production of NGF at the level of the blood-brain barrier, whether acting as an immunomodulator or directly on neural cells, is another potential mechanism contributing to the magnetic resonance imaging-defined effect of interferon beta on brain atrophy when given early in the course of MS.

10.1001/archneur.62.4.563

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Citations (89)

Comparative morphology and phagocytic capacity of primary human adult microglia with time-lapse imaging

Journal of Neuroimmunology (2017)

Natalie Levtova Luke M. Healy Catalina M. Carvajal Gonczi Brandon Stopnicki Manon Blain

Monocyte

10.1016/j.jneuroim.2017.05.012

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Citations (12)

CD40 engagement stimulates IL-12P70 production by human microglial cells: Regulation by autocrine TNF

Journal of Neuroimmunology (1998)

Burkhard Becher Jack P. Antel Manon Blain

10.1016/s0165-5728(98)91264-4

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Citations (0)

Diverse injury responses of human oligodendrocyte to mediators implicated in multiple sclerosis

Brain (2022)

Florian Pernin Julia Xiao Xuan Luo Qiao‐Ling Cui Manon Blain Milton Guilherme Forestieri Fernandes

Abstract Early multiple sclerosis lesions feature relative preservation of oligodendrocyte cell bodies with dying back retraction of their myelinating processes. Cell loss occurs with disease progression. Putative injury mediators include metabolic stress (low glucose/nutrient), pro-inflammatory mediators (interferon γ and tumour necrosis factor α), and excitotoxins (glutamate). Our objective was to compare the impact of these disease relevant mediators on the injury responses of human mature oligodendrocytes. In the current study, we determined the effects of these mediators on process extension and survival of human brain derived mature oligodendrocytes in vitro and used bulk RNA sequencing to identify distinct effector mechanisms that underlie the responses. All mediators induced significant process retraction of the oligodendrocytes in dissociated cell culture. Only metabolic stress (low glucose/nutrient) conditions resulted in delayed (4–6 days) non-apoptotic cell death. Metabolic effects were associated with induction of the integrated stress response, which can be protective or contribute to cell injury dependent on its level and duration of activation. Addition of Sephin1, an agonist of the integrated stress response induced process retraction under control conditions and further enhanced retraction under metabolic stress conditions. The antagonist ISRIB restored process outgrowth under stress conditions, and if added to already stressed cells, reduced delayed cell death and prolonged the period in which recovery could occur. Inflammatory cytokine functional effects were associated with activation of multiple signalling pathways (including Jak/Stat-1) that regulate process outgrowth, without integrated stress response induction. Glutamate application produced limited transcriptional changes suggesting a contribution of effects directly on cell processes. Our comparative studies indicate the need to consider both the specific injury mediators and the distinct cellular mechanisms of responses to them by human oligodendrocytes to identify effective neuroprotective therapies for multiple sclerosis.

Excitotoxicity

10.1093/brain/awac075

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Citations (19)

MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes

Journal of Neuroinflammation (2022)

Nicholas W. Kieran Rahul Suresh Marie‐France Dorion Adam MacDonald Manon Blain

Abstract Background Astrocytes are the most numerous glial cell type with important roles in maintaining homeostasis and responding to diseases in the brain. Astrocyte function is subject to modulation by microRNAs (miRs), which are short nucleotide strands that regulate protein expression in a post-transcriptional manner. Understanding the miR expression profile of astrocytes in disease settings provides insight into the cellular stresses present in the microenvironment and may uncover pathways of therapeutic interest. Methods Laser-capture microdissection was used to isolate human astrocytes surrounding stroke lesions and those from neurological control tissue. Astrocytic miR expression profiles were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Primary human fetal astrocytes were cultured under in vitro stress conditions and transfection of a miR mimic was used to better understand how altered levels of miR-210 affect astrocyte function. The astrocytic response to stress was studied using qPCR, enzyme-linked immunosorbent assays (ELISAs), measurement of released lactate, and Seahorse. Results Here, we measured miR expression levels in astrocytes around human ischemic stroke lesions and observed differential expression of miR-210 in chronic stroke astrocytes compared to astrocytes from neurological control tissue. We also identified increased expression of miR-210 in mouse white matter tissue around middle cerebral artery occlusion (MCAO) brain lesions. We aimed to understand the role of miR-210 in primary human fetal astrocytes by developing an in vitro assay of hypoxic, metabolic, and inflammatory stresses . A combination of hypoxic and inflammatory stresses was observed to upregulate miR-210 expression. Transfection with miR-210-mimic (210M) increased glycolysis, enhanced lactate export, and promoted an anti-inflammatory transcriptional and translational signature in astrocytes. Additionally, 210M transfection resulted in decreased expression of complement 3 ( C3 ) and semaphorin 5b (Sema5b) . Conclusions We conclude that miR-210 expression in human astrocytes is modulated in response to ischemic stroke disease and under in vitro stress conditions, supporting a role for miR-210 in the astrocytic response to disease conditions. Further, the anti-inflammatory and pro-glycolytic impact of miR-210 on astrocytes makes it a potential candidate for further research as a neuroprotective agent.

Human brain

10.1186/s12974-021-02373-y

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Citations (24)

Reduction of the Peripheral Blood CD56bright NK Lymphocyte Subset in FTY720-Treated Multiple Sclerosis Patients

The Journal of Immunology (2011)

Trina Johnson Barbara L. Evans Bryce A. Durafourt Manon Blain Yves Lapierre

FTY720 (fingolimod) treatment of multiple sclerosis (MS) results in lymphopenia due to increased recruitment into and decreased egress from secondary lymphoid organs of CCR7(+) lymphocytes. Although absolute numbers of NK lymphocytes were reported as being unaltered in FTY720-treated MS patients (MS-FTY), such analyses did not detect a change in a minor subset. Because expression of CCR7 has been described on CD56(bright) NK cells, a minority population of NK cells, we investigated the effect of FTY720 treatment on the phenotype and function of human NK cells in the peripheral circulation of MS patients. MS-FTY patients displayed a decreased proportion of peripheral CD56(bright)CD62L(+)CCR7(+) NK cells compared with untreated MS and healthy donors. In vitro treatment with FTY720-P increased migration of untreated donor NK cells to CXCL12 while reducing the response to CX3CL1 with similar migration responses seen in NK cells from MS-FTY patients. FTY720-P inhibited sphingosine 1-phosphate-directed migration of CD56(bright) and CD56(dim) NK cells subsets from untreated healthy donors. IL-12- and IL-15-stimulated NK cells from MS-FTY patients displayed similar capacity to produce IFN-γ, TNF, IL-10, and MIP-1α cytokines/chemokines compared with NK cells from untreated healthy donors and displayed comparable levels of degranulation in response to K562 tumor cells compared with untreated donors. Subset alterations and function of NK cell populations will need to be considered as part of assessing overall immunosurveillance capacity of patients with MS who will receive sustained FTY720 therapy.

NKG2D

10.4049/jimmunol.1003823

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Citations (58)

Analysis of the microglia transcriptome across the human lifespan using single cell RNA sequencing

Journal of Neuroinflammation (2023)

Moein Yaqubi Adam M.R. Groh Marie‐France Dorion Elia Afanasiev Julia Xiao Xuan Luo

Microglia are tissue resident macrophages with a wide range of critically important functions in central nervous system development and homeostasis.In this study, we aimed to characterize the transcriptional landscape of ex vivo human microglia across different developmental ages using cells derived from pre-natal, pediatric, adolescent, and adult brain samples. We further confirmed our transcriptional observations using ELISA and RNAscope.We showed that pre-natal microglia have a distinct transcriptional and regulatory signature relative to their post-natal counterparts that includes an upregulation of phagocytic pathways. We confirmed upregulation of CD36, a positive regulator of phagocytosis, in pre-natal samples compared to adult samples in situ. Moreover, we showed adult microglia have more pro-inflammatory signature compared to microglia from other developmental ages. We indicated that adult microglia are more immune responsive by secreting increased levels of pro-inflammatory cytokines in response to LPS treatment compared to the pre-natal microglia. We further validated in situ up-regulation of IL18 and CXCR4 in human adult brain section compared to the pre-natal brain section. Finally, trajectory analysis indicated that the transcriptional signatures adopted by microglia throughout development are in response to a changing brain microenvironment and do not reflect predetermined developmental states.In all, this study provides unique insight into the development of human microglia and a useful reference for understanding microglial contribution to developmental and age-related human disease.

Human brain

10.1186/s12974-023-02809-7

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Citations (16)