Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis.

Abstract:

:Neuroaxonal degeneration is a pathological hallmark of multiple sclerosis (MS) contributing to irreversible neurological disability. Pathological mechanisms leading to axonal damage include autoimmunity to neuronal antigens. In actively demyelinating lesions, myelin is phagocytosed by microglia and blood-borne macrophages, whereas the fate of degenerating or damaged axons is unclear. Phagocytosis is essential for clearing neuronal debris to allow repair and regeneration. However, phagocytosis may lead to antigen presentation and autoimmunity, as has been described for neuroaxonal antigens. Despite this notion, it is unknown whether phagocytosis of neuronal antigens occurs in MS. Here, we show using novel, well-characterized antibodies to axonal antigens, that axonal damage is associated with HLA-DR expressing microglia/macrophages engulfing axonal bulbs, indicative of axonal damage. Neuronal proteins were frequently observed inside HLA-DR(+) cells in areas of axonal damage. In vitro, phagocytosis of neurofilament light (NF-L), present in white and gray matter, was observed in human microglia. The number of NF-L or myelin basic protein (MBP) positive cells was quantified using the mouse macrophage cell line J774.2. Intracellular colocalization of NF-L with the lysosomal membrane protein LAMP1 was observed using confocal microscopy confirming that NF-L is taken up and degraded by the cell. In vivo, NF-L and MBP was observed in cerebrospinal fluid cells from patients with MS, suggesting neuronal debris is drained by this route after axonal damage. In summary, neuroaxonal debris is engulfed, phagocytosed, and degraded by HLA-DR(+) cells. Although uptake is essential for clearing neuronal debris, phagocytic cells could also play a role in augmenting autoimmunity to neuronal antigens.

journal_name

Glia

journal_title

Glia

authors

Huizinga R,van der Star BJ,Kipp M,Jong R,Gerritsen W,Clarner T,Puentes F,Dijkstra CD,van der Valk P,Amor S

doi

10.1002/glia.22276

subject

Has Abstract

pub_date

2012-03-01 00:00:00

pages

422-31

issue

3

eissn

0894-1491

issn

1098-1136

journal_volume

60

pub_type

杂志文章

相关文献

GLIA文献大全
  • Endothelin-1 increases 2-arachidonoyl glycerol (2-AG) production in astrocytes.

    abstract::Astrocytes play an important role in neuroprotective responses. Recent studies indicate that endothelin-1, a neuropeptide upregulated during brain injury, increases levels of the endocannabinoid anandamide, a lipid with neuroprotective properties, in astrocytes in primary cultures. However, whether this neuropeptide a...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.10270

    authors: Walter L,Stella N

    更新日期:2003-10-01 00:00:00

  • Differential contributions of microglial and neuronal IKKβ to synaptic plasticity and associative learning in alert behaving mice.

    abstract::Microglia are CNS resident immune cells and a rich source of neuroactive mediators, but their contribution to physiological brain processes such as synaptic plasticity, learning, and memory is not fully understood. In this study, we used mice with partial depletion of IκB kinase β, the main activating kinase in the in...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.22756

    authors: Kyrargyri V,Vega-Flores G,Gruart A,Delgado-García JM,Probert L

    更新日期:2015-04-01 00:00:00

  • Hypoglycemia, brain energetics, and hypoglycemic neuronal death.

    abstract::Hypoglycemia is a common and serious problem among diabetic patients receiving treatment with insulin or other glucose-lowering drugs. Moderate hypoglycemia impairs neurological function, and severe hypoglycemia leads to death of selectively vulnerable neurons. Recent advances have shed new light on the underlying pro...

    journal_title:Glia

    pub_type: 杂志文章,评审

    doi:10.1002/glia.20440

    authors: Suh SW,Hamby AM,Swanson RA

    更新日期:2007-09-01 00:00:00

  • Trisialoganglioside GT1b induces in vivo degeneration of nigral dopaminergic neurons: role of microglia.

    abstract::We recently showed that trisialoganglioside (GT1b) induces cell death of dopaminergic neurons in rat mesencephalic cultures (Chung et al., Neuroreport 12:611-614, 2001). The present study examines the in vivo neurotoxic effects of GT1b on dopaminergic neurons in the substantia nigra (SN) of Sprague-Dawley rats. Seven ...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.10047

    authors: Ryu JK,Shin WH,Kim J,Joe EH,Lee YB,Cho KG,Oh YJ,Kim SU,Jin BK

    更新日期:2002-04-01 00:00:00

  • Sequence of oligodendrocyte development in the human fetal telencephalon.

    abstract::Oligodendrocytes (OL), cells that myelinate axons in the CNS, differentiate from early to late oligodendrocyte progenitor cells (OPC) to become mature OL. Unlike the case in the rodent brain, myelin formation starts prenatally in the human brain, but the sequence of OL development and the onset of myelination are not ...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.20134

    authors: Jakovcevski I,Zecevic N

    更新日期:2005-03-01 00:00:00

  • Differential expression of neuropsin and protease M/neurosin in oligodendrocytes after injury to the spinal cord.

    abstract::Neuropsin and protease M/neurosin are serine proteases expressed by neurons and glial cells, and serve a variety of functions in the central nervous system (CNS). The current study demonstrates changes in the expression of these proteases following hemisection of the mouse spinal cord. Within unlesioned spinal cord, n...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.20058

    authors: Terayama R,Bando Y,Takahashi T,Yoshida S

    更新日期:2004-11-01 00:00:00

  • Calcium-mobilizing and electrophysiological effects of bradykinin on cortical astrocyte subtypes in culture.

    abstract::The possible consequences of activating bradykinin (Bk) receptors on identified astrocyte subtypes derived from rat cortex have been investigated in terms of: 1) mobilization of intracellular Ca2+; and 2) electrophysiological response. Bk induced a rapid, transient rise in intracellular Ca2+ in 63% of cortical type-1-...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.440090405

    authors: Stephens GJ,Cholewinski AJ,Wilkin GP,Djamgoz MB

    更新日期:1993-12-01 00:00:00

  • ED2-positive perivascular cells act as neuronophages during delayed neuronal loss in the facial nucleus of the rat.

    abstract::Injection of Fluoro-Gold (FG) into the whisker pad of rats yields a stable retrograde labeling of facial motoneurons. After removal of 10 mm from the facial nerve the microglia phagocytose the FG-prelabeled dead neurons and assume the label. A subsequent brightfield immunostaining of the sections with HRP-DAB as end-p...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/(SICI)1098-1136(199602)16:2<129::AID-GLIA5

    authors: Angelov DN,Neiss WF,Streppel M,Walther M,Guntinas-Lichius O,Stennert E

    更新日期:1996-02-01 00:00:00

  • Transient hypoxia/hypoglycemia upregulates endothelin B receptors in cultured rat astrocytes.

    abstract::Endothelins are potent vasoactive peptides that bind to their specific receptors, playing an important role in the CNS under physiological and pathophysiological conditions. Astrocytes, which have been shown to express these receptors, also have a considerable role to play under physiological and pathophysiological co...

    journal_title:Glia

    pub_type: 杂志文章

    doi:

    authors: Shibaguchi H,Himeno A,Shigematsu K,Kataoka Y,Niwa M

    更新日期:2000-07-01 00:00:00

  • A DAP12-dependent signal promotes pro-inflammatory polarization in microglia following nerve injury and exacerbates degeneration of injured neurons.

    abstract::Under pathological conditions, activated microglia play paradoxical roles and could have neurotoxic or neuroprotective effects. However, the signal determining how activated microglia affects the fate of neuronal cells remains largely unknown. Here we demonstrate that DNAX-activating protein of 12 kDa (DAP12), a trans...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.22802

    authors: Kobayashi M,Konishi H,Takai T,Kiyama H

    更新日期:2015-06-01 00:00:00

  • Insulin-like growth factor I: a mitogen for rat Schwann cells in the presence of elevated levels of cyclic AMP.

    abstract::To develop effective procedures for improving the regeneration of peripheral nerves and for preventing the formation of neurofibromas, it is necessary to identify the different mitogens that stimulate the proliferation of Schwann cells. Insulin-like growth factor I (IGF-I), which is a potent autocrine growth factor in...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.440080403

    authors: Schumacher M,Jung-Testas I,Robel P,Baulieu EE

    更新日期:1993-08-01 00:00:00

  • Microglia suppress the secondary progression of autoimmune encephalomyelitis.

    abstract::Secondary progressive multiple sclerosis (SPMS) is an autoimmune disease of the central nervous system (CNS) characterized by progressive motor dysfunction, sensory deficits, and visual problems. The pathological mechanism of SPMS remains poorly understood. In this study, we investigated the role of microglia, immune ...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.23640

    authors: Tanabe S,Saitoh S,Miyajima H,Itokazu T,Yamashita T

    更新日期:2019-09-01 00:00:00

  • Schwann cell heparan sulfate proteoglycans play a critical role in glial growth factor/neuregulin signaling.

    abstract::Glial growth factors are proteins encoded by the neuregulin gene and are thought to signal via receptor tyrosine kinases. Many neuregulin gene products bind heparin, and we hypothesize that affinity for heparin may implicate cell surface heparan sulfate proteoglycans (HeSPGs) as co-receptors for the soluble neuregulin...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/(SICI)1098-1136(199605)17:1<28::AID-GLIA3>

    authors: Sudhalter J,Whitehouse L,Rusche JR,Marchionni MA,Mahanthappa NK

    更新日期:1996-05-01 00:00:00

  • Neuronal hyperactivity induces astrocytic expression of neurocan in the adult rat hippocampus.

    abstract::Extracellular matrix molecules are involved in the cellular functions of proliferation, migration, morphological differentiation, and synaptic plasticity. One candidate molecule of the extracellular matrix is the chondroitin sulfate proteoglycan neurocan. To determine whether neurocan expression is regulated by neuron...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.20329

    authors: Schwarzacher SW,Vuksic M,Haas CA,Burbach GJ,Sloviter RS,Deller T

    更新日期:2006-05-01 00:00:00

  • Zn2+ -induced ERK activation mediates PARP-1-dependent ischemic-reoxygenation damage to oligodendrocytes.

    abstract::Much of the cell death following episodes of anoxia and ischemia in the mammalian central nervous system has been attributed to extracellular accumulation of glutamate and ATP, which causes a rise in [Ca(2+)](i), loss of mitochondrial potential, and cell death. However, restoration of blood flow and reoxygenation are ...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.22441

    authors: Domercq M,Mato S,Soria FN,Sánchez-gómez MV,Alberdi E,Matute C

    更新日期:2013-03-01 00:00:00

  • Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS).

    abstract::Astrocytic proliferation and hypertrophy (astrogliosis) are associated with neuronal injury. However, neither the temporal nor the spatial relationship between astrocytes and injured neurons is clear, especially in neurodegenerative diseases. We investigated these questions in a mouse amyotrophic lateral sclerosis (AL...

    journal_title:Glia

    pub_type: 杂志文章

    doi:

    authors: Levine JB,Kong J,Nadler M,Xu Z

    更新日期:1999-12-01 00:00:00

  • Early loss of astrocytes after experimental traumatic brain injury.

    abstract::Neuronal-glial interactions are important for normal brain function and contribute to the maintenance of the brain's extracellular environment. Damage to glial cells following traumatic brain injury (TBI) could therefore be an important contributing factor to brain dysfunction and neuronal injury. We examined the earl...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.10283

    authors: Zhao X,Ahram A,Berman RF,Muizelaar JP,Lyeth BG

    更新日期:2003-11-01 00:00:00

  • Upregulation of phospholipase D in astrocytes in response to transient forebrain ischemia.

    abstract::Previous in vitro studies using cell cultures or brain slices have demonstrated that phospholipase D (PLD) in the nervous system is involved in the signaling mechanism in response to a variety of agonists. However, little is known about the pathophysiological role of PLD-mediated signaling in the adult brain. We exami...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/(sici)1098-1136(200005)30:3<311::aid-glia1

    authors: Lee MY,Kim SY,Min DS,Choi YS,Shin SL,Chun MH,Lee SB,Kim MS,Jo YH

    更新日期:2000-05-01 00:00:00

  • CXXC5 plays a role as a transcription activator for myelin genes on oligodendrocyte differentiation.

    abstract::Myelination in corpus callosum plays important role for normal brain functions by transferring neurological information between various brain regions. However, the factors controlling expression of myelin genes in myelination are poorly understood. Here, CXXC5, a recently identified protein with CXXC-type zinc finger ...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.22932

    authors: Kim MY,Kim HY,Hong J,Kim D,Lee H,Cheong E,Lee Y,Roth J,Kim DG,Min do S,Choi KY

    更新日期:2016-03-01 00:00:00

  • Purinergic receptors in microglia: functional modal shifts of microglia mediated by P2 and P1 receptors.

    abstract::Microglia are sensitive to environmental changes and are immediately transformed into several phenotypes. For such dynamic "modal shifts", purinergic receptors have central roles. When microglia sense ATP/ADP leaked from injured cells by P2Y(12) receptors, they are transformed into a moving phenotype, showing process ...

    journal_title:Glia

    pub_type: 杂志文章,评审

    doi:10.1002/glia.22358

    authors: Koizumi S,Ohsawa K,Inoue K,Kohsaka S

    更新日期:2013-01-01 00:00:00

  • Simvastatin regulates oligodendroglial process dynamics and survival.

    abstract::Simvastatin, a lipophilic statin that crosses the blood-brain barrier, is being evaluated as a potential therapy for multiple sclerosis (MS) due to its anti-inflammatory properties. We assessed the effects of simvastatin on cultures of rat newborn and human fetal oligodendrocyte progenitor cells (OPCs) and human adult...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.20441

    authors: Miron VE,Rajasekharan S,Jarjour AA,Zamvil SS,Kennedy TE,Antel JP

    更新日期:2007-01-15 00:00:00

  • Role of the extracellular matrix in myelination of peripheral nerve.

    abstract::Assembly of the extracellular matrix (ECM) has been tightly linked to compact myelin formation in the peripheral nervous system. We recently demonstrated that myelination of dorsal root ganglion (DRG) axons by Schwann cells may occur in the absence of basal lamina. We have now determined whether laminin deposition occ...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.1068

    authors: Podratz JL,Rodriguez E,Windebank AJ

    更新日期:2001-07-01 00:00:00

  • Spatial arrangement of microglia in the mouse hippocampus: a stereological study in comparison with astrocytes.

    abstract::Microglia are classically considered to be immune cells in the brain, but have now been proven to be involved in neuronal activity as well. Here we stereologically analyzed the spatial arrangement of microglia in the mouse hippocampus. First, we estimated the numerical densities (NDs) of microglia identified by ionize...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.20552

    authors: Jinno S,Fleischer F,Eckel S,Schmidt V,Kosaka T

    更新日期:2007-10-01 00:00:00

  • Microglia as modulators of cognition and neuropsychiatric disorders.

    abstract::It has become evident recently only that microglia are not only responsible for immunomodulatory functions in the brain but represent vital components of the larger synaptic formation, which also includes pre and postsynaptic neurones as well as astrocytes. Microglia critically contribute to CNS homeostasis by their a...

    journal_title:Glia

    pub_type: 杂志文章,评审

    doi:10.1002/glia.22372

    authors: Blank T,Prinz M

    更新日期:2013-01-01 00:00:00

  • Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor.

    abstract::Microglia respond rapidly to injury, increasing their synthesis and release of inflammatory mediators, many of which contribute to the maintenance of persistent pain following CNS or PNS injury. We have recently shown that the lysosomal cysteine protease Cathepsin S (CatS) expressed by spinal microglia is vital for th...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.21042

    authors: Clark AK,Wodarski R,Guida F,Sasso O,Malcangio M

    更新日期:2010-11-01 00:00:00

  • Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn.

    abstract::The mechanisms underlying neuropathic pain are poorly understood. However, several studies have implied a role for reactive microglia located in the dorsal horn in neuropathic pain. To clarify the roles of activated microglia in neuropathic pain, we investigated the interactions among microglia and other neural compon...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.21053

    authors: Maeda M,Tsuda M,Tozaki-Saitoh H,Inoue K,Kiyama H

    更新日期:2010-11-15 00:00:00

  • Inositol 1,4,5-trisphosphate receptor type 2-independent Ca2+ release from the endoplasmic reticulum in astrocytes.

    abstract::Accumulating evidence indicates that astrocytes are actively involved in the physiological and pathophysiological functions of the brain. Intracellular Ca2+ signaling, especially Ca2+ release from the endoplasmic reticulum (ER), is considered to be crucial for the regulation of astrocytic functions. Mice with genetic ...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.23531

    authors: Okubo Y,Kanemaru K,Suzuki J,Kobayashi K,Hirose K,Iino M

    更新日期:2019-01-01 00:00:00

  • Selective upregulation of inducible nitric oxide synthase (iNOS) by lipopolysaccharide (LPS) and cytokines in microglia: in vitro and in vivo studies.

    abstract::A role for free radicals has been proposed in infectious brain disease, where resident microglia cells upregulate the inducible nitric oxide synthase isoform (iNOS), and thus are capable of producing nitric oxide at enhanced rates. Using the constitutively expressed NADPH oxidase, microglial cells can generate superox...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/1098-1136(200010)32:1<51::aid-glia50>3.0.c

    authors: Possel H,Noack H,Putzke J,Wolf G,Sies H

    更新日期:2000-10-01 00:00:00

  • Localization of annexin II in the paranodal regions and Schmidt-Lanterman incisures in the peripheral nervous system.

    abstract::Annexin II (AX II) is a member of the family of calcium-dependent actin- and phospholipid-binding proteins implicated in numerous intracellular functions such as signal transduction, membrane trafficking, and mRNA transport, as well as in the regulation of membrane/cytoskeleton contacts and extracellular functions. AX...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.20529

    authors: Hayashi A,Nakashima K,Yamagishi K,Hoshi T,Suzuki A,Baba H

    更新日期:2007-08-01 00:00:00

  • Oligodendrocytes expressing exclusively the DM20 isoform of the proteolipid protein gene: myelination and development.

    abstract::Oligodendroglia and Schwann cells synthesize myelin-specific proteins and lipids for the assembly of the highly organized myelin membrane of the motor-sensory axons in the central (CNS) and peripheral nervous system (PNS), respectively, allowing rapid saltatory conduction. The isoforms of the main myelin proteins, the...

    journal_title:Glia

    pub_type: 杂志文章

    doi:10.1002/glia.10014

    authors: Spörkel O,Uschkureit T,Büssow H,Stoffel W

    更新日期:2002-01-01 00:00:00