Microglial clearance function in health and disease

doi:10.1016/j.neuroscience.2008.06.046

Neuroscience

Volume 158, Issue 3, 6 February 2009, Pages 1030-1038

https://doi.org/10.1016/j.neuroscience.2008.06.046 Get rights and content

Abstract

Microglial cells are of hematopoietic origin, populate the CNS during early development and form the brain's innate immune cell type. Besides their well-known role in immune defense, microglia have an active and homeostatic function in the normal CNS based on high motility of their ramified processes and endocytic clearance of apoptotic vesicular material. During development microglia contribute to the reorganization of neuronal connections, however microglia have also pivotal roles during acute and chronic neurodegeneration. Microglia become attracted to site of injury by nucleotides released from damaged neurons. Scavenger receptors expressed on microglia bind to debris and microglial phagocytic receptors signal via immunoreceptor tyrosine-based activation motif (ITAM) –containing adaptor proteins to promote phagocytosis of extracellular material. Insufficient clearance by microglia appears to be prevalent in neurodegenerative diseases such as Alzheimer’s disease.

Section snippets

Microglial motility

Microglial cells are of hematopoietic origin and populate the CNS during early development. In the adult mouse approximately 10% of all brain cells are microglia. Microglial cells are responsible for the first line of immune defense in the CNS. To exert this task microglial cells are highly ramified. A multitude of microglial processes extend over non-overlapping territories, thus covering the entire CNS parenchyma. Microglia are found to be activated under several pathological conditions

Microglial phagocytosis

Microglial phagocytosis is a highly coordinated process, which is mainly regulated by signals that microglia receive from their environment. Microglia express distinct types of receptors which are either involved in the phagocytosis of pathogenic organisms such as TLRs or scavenger receptors for clearance of apoptotic cellular debris such as receptors recognizing phosphatidylserine (PtdSer) residues. As mentioned before, both reactions substantially differ in their inflammatory response in the

Restructuring of neuronal connections during development

Excess production of neurons and loss by apoptosis are evident in most regions of the developing CNS. Microglial cells have populated the CNS before this neuronal loss occurs and are involved in the removal of cellular debris and dead cell corpuses. It has been shown in the developing mouse cerebellum that apoptotic Purkinje cells were engulfed after being contacted by spreading processes of microglial cells (Marin-Teva et al., 2004). Interestingly apoptosis of Purkinje cells in cerebellar

Mechanical injury

Following acute lesion microglia respond to this trigger with a synchronized and dynamic immune response. They migrate toward the lesion site and remove the degenerated tissue. A study in an animal model of spinal cord transection supported the view that the innate immune system might beneficially contribute to the repair of the injured CNS (Rapalino et al., 1998). Rats partly regained their locomotor activity after local implantation of macrophages pre-stimulated on peripheral nerves. It was

Alzheimer’s disease (AD)

The role of microglia in the pathogenesis of AD is still controversial. Microglia play a neuroprotective role in AD by secreting proteolytic enzymes that degrade Aβ and expressing receptors which are involved in the clearance and phagocytosis of Aβ. However, microglia might also contribute to disease progression by producing neurotoxins including reactive oxygen species and pro-inflammatory cytokines. In a transgenic mouse model of AD bone marrow–derived cells were recruited to senile plaques

Conclusion

Microglia contribute to the homeostasis of the CNS by phagocytosis of apoptotic cells and degenerated tissue. Signals for attraction of microglia and engulfment of apoptotic cells are emerging and need to be identified further. When cells undergo apoptosis, PtdSer is translocated to the outer leaflet, where it becomes accessible to microglia. Microglia recognize PtdSer by specific microglial receptors and start clearance of apoptotic debris. The role of microglial phagocytosis in CNS

Acknowledgments

The Neural Regeneration Group at the University Bonn is supported by the Hertie-Foundation, the Walter-und-Ilse-Rose-Foundation, the DFG (SFB704, KFO177) and the EU (LSHM-CT-2005-018637).

References (67)

T. Awasaki et al.
Engulfing action of glial cells is required for programmed axon pruning during Drosophila metamorphosis
Curr Biol
(2004)
T. Awasaki et al.
Essential role of the apoptotic cell engulfment genes draper and ced-6 in programmed axon pruning during Drosophila metamorphosis
Neuron
(2006)
K. Biber et al.
Neuronal ‘on’ and ‘off’ signals control microglia
Trends Neurosci
(2007)
D.L. Bishop et al.
Axon branch removal at developing synapses by axosome shedding
Neuron
(2004)
K. Broadie
Axon pruning: an active role for glial cells
Curr Biol
(2004)
J.R. Conde et al.
Effect of aging on the microglial response to peripheral nerve injury
Neurobiol Aging
(2006)
R.A. Corriveau et al.
Regulation of class I MHC gene expression in the developing and mature CNS by neural activity
Neuron
(1998)
S. Cullheim et al.
The microglial networks of the brain and their role in neuronal network plasticity after lesion
Brain Res Rev
(2007)
M. Dubois-Dalcq et al.
Enhancing central nervous system remyelination in multiple sclerosis
Neuron
(2005)
J.M. Frade et al.
Microglia-derived nerve growth factor causes cell death in the developing retina
Neuron
(1998)

N. Kobayashi et al.

TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells

Immunity

(2007)

M.R. Kotter et al.

Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression

Neurobiol Dis

(2005)

T.M. Malm et al.

Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice

Neurobiol Dis

(2005)

J.L. Marin-Teva et al.

Microglia promote the death of developing Purkinje cells

Neuron

(2004)

H. Neumann et al.

Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis

J Neuroimmunol

(2007)

J. Paloneva et al.

Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype

Am J Hum Genet

(2002)

K.S. Ravichandran

‘Recruitment signals’ from apoptotic cells: invitation to a quiet meal

Cell

(2003)

C. Santiago et al.

Structures of T cell immunoglobulin mucin protein 4 show a metal-ion-dependent ligand binding site where phosphatidylserine binds

Immunity

(2007)

C. Santiago et al.

Structures of T cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family

Immunity

(2007)

A.R. Simard et al.

Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease

Neuron

(2006)

B. Stevens et al.

The classical complement cascade mediates CNS synapse elimination

Cell

(2007)

W.J. Streit

Microglial senescence: does the brain's immune system have an expiration date?

Trends Neurosci

(2006)

S. Thams et al.

MHC class I expression and synaptic plasticity after nerve lesion

Brain Res Rev

(2008)

Q. Wang et al.

The inflammatory response in stroke

J Neuroimmunol

(2007)

R.J. Watts et al.

Axon pruning during Drosophila metamorphosis: evidence for local degeneration and requirement of the ubiquitin-proteasome system

Neuron

(2003)

R.M. Yates et al.

Phagosome maturation proceeds independently of stimulation of toll-like receptors 2 and 4

Immunity

(2005)

Z. Zhou et al.

CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans

Cell

(2001)

J.M. Blander et al.

Regulation of phagosome maturation by signals from toll-like receptors

Science

(2004)

T. Bolmont et al.

Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance

J Neurosci

(2008)

M. Britschgi et al.

Immune cells may fend off Alzheimer disease

Nat Med

(2007)

A.E. Cardona et al.

Control of microglial neurotoxicity by the fractalkine receptor

Nat Neurosci

(2006)

M. Colonna

TREMs in the immune system and beyond

Nat Rev Immunol

(2003)

D. Davalos et al.

ATP mediates rapid microglial response to local brain injury in vivo

Nat Neurosci

(2005)

Cited by (260)

Stress- and drug-induced neuroimmune signaling as a therapeutic target for comorbid anxiety and substance use disorders
2022, Pharmacology and Therapeutics
Stress and substance use disorders remain two of the most highly prevalent psychiatric conditions and are often comorbid. While individually these conditions have a debilitating impact on the patient and a high cost to society, the symptomology and treatment outcomes are further exacerbated when they occur together. As such, there are few effective treatment options for these patients, and recent investigation has sought to determine the neural processes underlying the co-occurrence of these disorders to identify novel treatment targets. One such mechanism that has been linked to stress- and addiction-related conditions is neuroimmune signaling. Increases in inflammatory factors across the brain have been heavily implicated in the etiology of these disorders, and this review seeks to determine the nature of this relationship. According to the “dual-hit” hypothesis, also referred to as neuroimmune priming, prior exposure to either stress or drugs of abuse can sensitize the neuroimmune system to be hyperresponsive when exposed to these insults in the future. This review completes an examination of the literature surrounding stress-induced increases in inflammation across clinical and preclinical studies along with a summarization of the evidence regarding drug-induced alterations in inflammatory factors. These changes in neuroimmune profiles are also discussed within the context of their impact on the neural circuitry responsible for stress responsiveness and addictive behaviors. Further, this review explores the connection between neuroimmune signaling and susceptibility to these conditions and highlights the anti-inflammatory pharmacotherapies that may be used for the treatment of stress and substance use disorders.
Microglia contribute to the postnatal development of cortical somatostatin-positive inhibitory cells and to whisker-evoked cortical activity
2022, Cell Reports
Citation Excerpt :
Whether a similar mechanism is in place for inhibitory cells is still largely unknown. Microglia cells are the resident immune cells of the central nervous system (Ginhoux et al., 2013; Napoli and Neumann, 2009) and participate in both synapse formation (Lim et al., 2013; Miyamoto et al., 2016) and elimination (Hoshiko et al., 2012; Paolicelli et al., 2011; Schafer et al., 2012). Recent work has identified some of the molecular pathways involved in the interaction between microglia and excitatory neurons (Cong et al., 2020; Filipello et al., 2018; Gunner et al., 2019; Lehrman et al., 2018; Li et al., 2020; Paolicelli et al., 2011; Schafer et al., 2012; Stevens et al., 2007).
Microglia play a key role in shaping the formation and refinement of the excitatory network of the brain. However, less is known about whether and how they organize the development of distinct inhibitory networks. We find that microglia are essential for the proper development of somatostatin-positive (SST⁺) cell synapses during the second postnatal week. We further identify a pair of molecules that act antagonistically to one another in the organization of SST⁺ cell axonal elaboration. Whereas CX3CL1 acts to suppress axonal growth and complexity, CXCL12 promotes it. Assessing the functional importance of microglia in the development of cortical activity, we find that a whisker stimulation paradigm that drives SST⁺ cell activation leads to reduced cortical spiking in brains depleted of microglia. Collectively, our data demonstrate an important role of microglia in regulating the development of SST⁺ cell output early in life.
Defects of parvalbumin-positive interneurons in the ventral dentate gyrus region are implicated depression-like behavior in mice
2022, Brain, Behavior, and Immunity
Depression is an increasingly common but extremely serve mood disorder that remains poorly understood and inadequately treated. Fast-spiking parvalbumin-positive interneurons (PVIs), a subpopulation of GABAergic interneurons (GABA, g-aminobutyric acid), exhibit a widespread distribution throughout the hippocampus, and has been reported to play an important role in a variety of mental disorders. However, the relationship between depression and hippocampal PVIs remains unclear. Here in this present study, a series of experiments were conducted to clarify the potential relationship. Here, chronic unpredicted mild stress (CUMS) and Lipopolysaccharide (LPS) injection were introduced to induce depression-like behavior in mice, and led to a clear decline in PVIs numbers in the ventral hippocampal (vHPC), particularly in the ventral dentate gyrus (vDG) subfield. After a selectively removal of the PVIs in PV-ires-Cre::Ai14 mice, we confirmed that ablation of PVIs from the vDG induced depression-like behavior. Furthermore, we found that the removal of vDG-PVIs induced depression likely to be accounted for upregulation of neuroinflammation. These findings facilitate us better understand the role of hippocampal PVIs in depression.
The therapeutic potential and efficiency of Intracerebroventricular transplantation and intravenous injection of Mesenchymal stem cells in relieving Aß hallmarks and improving cognitive dysfunction in AD induced model
2021, Gene Reports
Alzheimer's disease (AD) has been considered a long-lasting, devastating public health concern due to a high folding increase in global aging percentage worldwide. Different approaches have been confined to cut down this high percentage of neurodegenerative disorder due to a lack of successful, efficient strategic protocol for AD treatment. One of these approaches is the transplantation or injection of mesenchymal stem cells (MSCs) due to their neuromodulatory, anti-inflammatory, and antioxidant actions.
To elucidate and determine whether intravenous (IV) or intracerebroventricular (ICV) administration of MSCs is the most efficient and successful method in engulfing amyloid-β plaques and improving cognitive defects.
The efficiency of MSCs was investigated on lipopolysaccharides (LPS) AD-induced rats. Thirty-two rats were randomly divided equally into four groups identified as a control group (C/G1), AD-induced group (AD/G2), intravenous AD-induced group (IV/G3), and ICV AD-induced group (ICV/G4). Amyloid-β, tau protein, tumor necrosis factor-α (TNF-α), interleukin (IL-10) were detected using the ELISA technique while MDA and GSH brain tissue level were detected colorimetry.
The histopathological examination of different brain tissues demonstrated the presence of Aβ plaques following LPS induction. Administration of both types of MSCs into AD-induced rats resulted in a significant decrease in the brain's hallmarks depositions, oxidative stress, and inflammatory factors with different degrees and efficiency.
The present study indicates the efficiency of both types of MSCs administration in improving AD subjects' cognitive defects with a more relevant efficiency following ICV administration, considering the risk to benefits ratio before taking inaction treatment initiation.
Phosphatidylserine synthase plays an essential role in glia and affects development, as well as the maintenance of neuronal function
2021, iScience
Phosphatidylserine (PS) is an integral component of eukaryotic cell membranes and organelles. The Drosophila genome contains a single PS synthase (PSS)-encoding gene (Pss) homologous to mammalian PSSs. Flies with Pss loss-of-function alleles show a reduced life span, increased bang sensitivity, locomotor defects, and vacuolated brain, which are the signs associated with neurodegeneration. We observed defective mitochondria in mutant adult brain, as well as elevated production of reactive oxygen species, and an increase in autophagy and apoptotic cell death. Intriguingly, glial-specific knockdown or overexpression of Pss alters synaptogenesis and axonal growth in the larval stage, causes developmental arrest in pupal stages, and neurodegeneration in adults. This is not observed with pan-neuronal up- or down-regulation. These findings suggest that precisely regulated expression of Pss in glia is essential for the development and maintenance of brain function. We propose a mechanism that underlies these neurodegenerative phenotypes triggered by defective PS metabolism.
Apoptotic neurons and amyloid-beta clearance by phagocytosis in Alzheimer's disease: Pathological mechanisms and therapeutic outlooks
2021, European Journal of Pharmacology
Neuronal survival and axonal renewal following central nervous system damage and in neurodegenerative illnesses, such as Alzheimer's disease (AD), can be enhanced by fast clearance of neuronal apoptotic debris, as well as the removal of amyloid beta (Aβ) by phagocytic cells through the process of efferocytosis. This process quickly inhibits the release of proinflammatory and antigenic autoimmune constituents, enhancing the formation of a microenvironment vital for neuronal survival and axonal regeneration. Therefore, the detrimental features associated with microglial phagocytosis uncoupling, such as the accumulation of apoptotic cells, inflammation and phagoptosis, could exacerbate the pathology in brain disease. Some mechanisms of efferocytosis could be targeted by several promising agents, such as curcumin, URMC-099 and Y–P30, which have emerged as potential treatments for AD. This review aims to investigate and update the current research regarding the signaling molecules and pathways involved in efferocytosis and how these could be targeted as a potential therapy in AD.

View all citing articles on Scopus

View full text

ReviewMicroglial clearance function in health and disease

Abstract

Section snippets

Microglial motility

Microglial phagocytosis

Restructuring of neuronal connections during development

Mechanical injury

Alzheimer’s disease (AD)

Conclusion

Acknowledgments

Curr Biol

Neuron

Trends Neurosci

Neuron

Curr Biol

Neurobiol Aging

Neuron

Brain Res Rev

Neuron

Neuron

Immunity

Neurobiol Dis

Neurobiol Dis

Neuron

J Neuroimmunol

Am J Hum Genet

Cell

Immunity

Immunity

Neuron

Cell

Trends Neurosci

Brain Res Rev

J Neuroimmunol

Neuron

Immunity

Cell

Regulation of phagosome maturation by signals from toll-like receptors

Science

Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance

J Neurosci

Immune cells may fend off Alzheimer disease

Nat Med

Control of microglial neurotoxicity by the fractalkine receptor

Nat Neurosci

TREMs in the immune system and beyond

Nat Rev Immunol

ATP mediates rapid microglial response to local brain injury in vivo

Nat Neurosci

Review
Microglial clearance function in health and disease