The Role Of Microglia And Macrophages In The PathoPhysiology Of The CNS
Stoll G, Jander S
Prog NeuroBiol 1999 Jun;58(3):233-47
Heinrich-Heine-University, Dept of Neurology, Dusseldorf, Germany
PMID# 10341362; UI# 99272908
Microglia are a major Glial component of the Central Nervous System (CNS) and are extremely sessile.
Only a subtype, the PeriVascular Microglia, are regularly replaced from the bone marrow in adult animals. Microglia respond to virtually any, even minor pathological events in the CNS.
In most pathological settings Microglia are aided by infiltrating Hematogenous Macrophages. Upon activation Microglia and Macrophages share most phenotypical markers and can exert similar Effector functions.
After transection of a CNS fiber tract Microglia are insufficiently activated and Hematogenous Macrophages do not significantly enter the degenerating Nerve stump.
Thereby Myelin debris that contains Neurite outgrowth inhibiting activity persists for long time.
This is in sharp contrast to the Peripheral Nervous System in which Hematogenous Macrophages are rapidly recruited in response to Axotomy and clear Myelin debris allowing regrowth of Axons from the proximal stump.
However, CNS lesion paradigms with breakdown of the Blood-Brain Barrier such as Cerebral Ischemia, Brain abscesses and stab wounds elicit prompt Microglial activation, Macrophage recruitment and debris clearance.
There is increasing evidence that Microglia play an active part in degenerative CNS Diseases. In Alzheimer's Disease activated Microglia appear to be involved in plaque formation.
In experimental Globoid Cell Dystrophy, T-Cell independent induction of Major Histocompatibility Complex Class II molecules on Microglia accelerates DeMyelination.
In AutoImmune Diseases, Microglia probably have dual functions. Microglia present Antigen to infiltrating T-Cells and exert Effector functions.
Thereby, locally augmenting Immune responses. On the other hand, Microglia have the capacity to downregulate T-Cell responses.
In the human Acquired ImmunoDeficiency Syndrome (AIDS) Virus infected Macrophages probably introduce the Virus to the CNS and in concert with Microglia are involved in the PathoPhysiology of the AIDS dementia complex.
Brain Cytokine Network And Novel Characteristics Of Microglia
Nihon Shinkei Seishin Yakurigaku Zasshi 1999 Oct;19(4):151-4
Japanese Science and Technology Corporation, Tokyo, Japan
PMID# 10681160; UI# 20141027
Microglia, Macrophage-like cells in the Central Nervous System (CNS), are multi-functional cells; they play an important role in the removal of dead cells or their remnants by Phagocytosis in CNS degeneration.
And are one of the important cells in the CNS Cytokine network to produce and respond to a variety of Cytokines.
Although little is known about Microglia in the normal CNS, it is obvious that they are quickly activated in all acute pathological events including Apoptosis, NeuroDegeneration and Inflammation.
Activation of Microglia in Apoptosis is a double-edged response; under severe Apoptotic conditions, Microglia act as scavengers removing tissue debris and inducing Apoptosis in damaged cells.
Whereas in more subtle injury they exert a surveillance function and might play a protective role. The transformation of resting Microglia into full-blown Phagocytes is strictly regulated.
To understand the molecular basis of controlling mechanisms of Microglia in Apoptosis, the study requires in vivo models.
For such purpose, we developed the Brain-targeting Gene delivery system using immortalized Microglia, which can facilitate investigation into the roles of particular Microglial Genes in Apoptosis and the Gene therapy of several Brain disorders.
Microglia Stimulate Naive T-Cell Differentiation Without Stimulating T-Cell Proliferation
Carson MJ, Sutcliffe JG, Campbell IL
J NeuroSci Res 1999 Jan 1;55(1):127-34
The Scripps Research Institute, Dept of Molecular Biology, La Jolla, California 92037, USA
PMID# 9890441; UI# 99105447
A major question relevant to the initiation and progression of inflammation and AutoImmune processes within the Central Nervous System (CNS) is:
Whether resident Microglia or only infiltrating Macrophage can productively interact with T-Cells that enter the CNS either actively through extravasation or passively through defects in the Blood-Brain Barrier (BBB).
We isolated Microglia and Macrophage from the Brains of healthy adult mice and transgenic mice that displayed many features of Multiple Sclerosis and HIV LeukoEncephalopathy.
Due to, the Astrocytic expression of InterLeukin-3 (IL-3) and compared their Antigen-Presenting Cell (APC) functions.
We found that unactivated Microglia isolated from healthy nontransgenic mice and activated Microglia isolated from transgenic siblings are relatively weak stimulators of naive T-Cell proliferation compared to Macrophage populations.
The APC function of activated, but not unactivated, Microglia could be increased by treatment acutely with LipoPolySaccharide (LPS)/Interferon-gamma (IFN-).
However, this treatment also induced the apparent production of ProstaGlandins, which reduced T-Cell proliferation when Indomethacin was absent from the assay cultures.
Strikingly, even in the absence of stimulated T-Cell proliferation, both unactivated and activated Microglia stimulated the differentiation of naive T-Cells into Th1 Effector Cells.
Although neither Microglial population was a more effective inducer than Macrophages or Splenic APCs.
Thus, while Microglia are clearly capable of productively interacting with naive T-Cells, Macrophages have a more robust APC function.
Differential Effects Of Central And Peripheral Nerves On Macrophages And Microglia
Zeev-Brann AB, Lazarov-Spiegler O, Brenner T, Schwartz M
Glia 1998 Jul;23(3):181-90
The Weizmann Institute of Science, Dept of NeuroBiology, Rehovot, Israel
PMID# 9633803; UI# 98295560
The poor ability of injured Central Nervous System (CNS) Axons to regenerate has been correlated, at least partially, with a limited and suppressed postinjury inflammatory response.
A key cell type in the inflammatory process is the Macrophage, which can respond in various ways, depending on the conditions of stimulation.
The aim of this study is to compare the activities of Macrophages or Microglia when encountering CNS and Peripheral Nervous Systems (PNS).
On the assumption that Nerve-related differences in the inflammatory response may have implications for tissue repair and thus for Nerve regeneration.
Phagocytic activity of Macrophages or of isolated Brain-derived Microglia was enhanced upon their exposure to Sciatic Nerve (PNS) segments, but inhibited by exposure to Optic Nerve (CNS) segments.
Similarly, Nitric Oxide production by Macrophages or Microglia was induced by Sciatic Nerve segments but not by Optic Nerve segments.
The previously demonstrated presence of a resident inhibitory activity in CNS Nerve, could account, at least in part, for the inhibited Phagocytic activity of blood-borne Macrophages in CNS Nerve as well as of Microglia resident in the Brain.
It seems that the CNS Microglia are reversibly ImmunoSuppressed by the CNS environment, at least with respect to the activities examined here.
It also appears from this study that the weak induction of early healing-related activities of Macrophages/Microglia in the environment of CNS might explain the subsequent failure of this environment to acquire growth-supportive properties in temporal and spatial synchrony with the needs of regrowing Axons.
Microglia: A Sensor For Pathological Events In The CNS
Trends NeuroSci 1996 Aug;19(8):312-8
Max-Planck-Institute of Psychiatry, Dept of Neuromorphology, Martinsried near Munich, Germany
PMID# 8843599; UI# 97000514
The most characteristic feature of Microglial Cells is their rapid activation in response to even minor pathological changes in the CNS.
Microglia activation is a key factor in the defence of the Neural Parenchyma against Infectious Diseases, Inflammation, Trauma, Ischemia, Brain Tumors and NeuroDegeneration.
Microglia activation occurs as a graded response in vivo. The transformation of Microglia into potentially CytoToxic cells is under strict control and occurs mainly in response to Neuronal or terminal degeneration, or both.
Activated Microglia are mainly scavenger cells but also perform various other functions in tissue repair and Neural regeneration.
They form a network of Immune alert resident Macrophages with a capacity for Immune surveillance and control.
Activated Microglia can destroy invading micro-organisms, remove potentially deleterious debris, promote tissue repair by secreting Growth Factors and thus facilitate the return to tissue Homeostasis.
An understanding of InterCellular signalling pathways for Microglia proliferation and activation could form a rational basis for targeted intervention on Glial reactions to injuries in the CNS.
Increased Levels Of IL-15 mRNA In Relapsing/Remitting Multiple Sclerosis Attacks
Blanco-Jerez C, Plaza JF, Masjuan J, Orensanz LM, Alvarez-Cermeno JC
J NeuroImmunol 2002 Jul;128(1-2):90-4
Hospital Ramon y Cajal, Department of NeuroBiology, Crta. Colmenar Km 9, Madrid 28034, Spain
IL-15 is a ProInflammatory Cytokine which has recently been implicated in Multiple Sclerosis (MS) pathogenesis, where it may play a role in the initiation and/or progression of the disease.
We have used Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) to study IL-15 mRNA levels in Peripheral Blood MonoNuclear Cells (PBMC) from healthy controls and Relapsing/Remitting MS (RR-MS) patients:
In a stable phase of the disease and during a bout, both before and after CorticoSteroid Treatment (CST).
IL-15 mRNA expression was found to be similar in controls and stable patients. We have detected an increased level of IL-15 mRNA in PBMC of patients with a relapse, which was maintained after CST.
We have also found an inverse correlation between PBMC IL-15 mRNA levels at the onset of the relapse and the time elapsed since the previous attack.
As well as an absence of correlation between IL-15 mRNA levels and the patient demographic and clinical characteristics.
Results in the present work further suggest a role for IL-15 in MS PathoPhysiology.
PET Visualization Of Microglia In Multiple Sclerosis Patients Using [11C]PK11195
Eur J Neurol 2003 May;10(3):257-64
Ghent University Hospital, Department of Neurology, Ghent, Belgium
Activated Microglia are involved in the Immune Response of Multiple Sclerosis (MS). The Peripheral Benzodiazepine Receptor (PBR) is expressed on Microglia and up-regulated after Neuronal injury.
[11C]PK11195 is a Positron Emission Tomography (PET) RadioLigand for the PBR.
The objective of the present study was to investigate [11C]PK11195 imaging in MS patients and its additional value over Magnetic Resonance Imaging (MRI) concerning the Immuno-PathoPhysiological process.
Seven healthy and 22 MS subjects were included. Semiquantitative [11C]PK11195 uptake values were assessed with normalization on Cortical Gray Matter.
Uptake in Gadolinium-lesions was significantly increased compared with normal White Matter.
Uptake in T2-lesions was generally decreased, suggesting a PBR down-regulation.
However, uptake values increased whenever a clinical or MR-relapse was present, suggestive for a dynamic process with a transient PBR up-regulation.
During disease progression, an increase of Normal-Appearing White Matter (NAWM) uptake was found, propagating NAWM as the possible real burden of disease.
In conclusion, [11C]PK11195 and PET are able to demonstrate inflammatory processes with Microglial involvement in MS.
Expression Of Major Histocompatibility Complex Class I Molecules On The Different Cell Types In Multiple Sclerosis Lesions
Hoftberger R, Aboul-Enein F, Brueck W, Lucchinetti C, Rodriguez M, Schmidbauer M, Jellinger K, Lassmann H
Brain Pathol 2004 Jan;14(1):43-50
Brain Research Institute, University of Vienna, Division of NeuroImmunology, Wien, Austria
Multiple Sclerosis is considered to be an Immune-mediated disease of the Central Nervous System, characterized by chronic inflammation, primary DeMyelination and Axonal damage.
The mechanisms of DeMyelination and Axonal injury are heterogeneous and complex. One possible mechanism is direct damage of Oligodendrocytes and Neurons by Class I MHC restricted CytoToxic T-Cells.
In this study we analyzed the expression of functional MHC Class I molecule complex, consisting of alpha-chain and beta2-MicroGlobulin, in a large sample of human autopsy material, containing 10 cases of acute MS, 10 cases of chronic active MS, 10 cases of chronic inactive MS and 21 controls.
To examine the expression of MHC class I and II molecules on the different cell-types in Brain, we used quantitative ImmunoHistoChemical techniques, double staining and confocal laser microscopy scans on paraffin embedded sections.
We found constitutive expression of MHC Class I molecule on Microglia and Endothelial Cells. A hierarchical up-regulation of MHC Class I was present on Astrocytes, Oligodendrocytes, Neurons and Axons, depending upon the severity of the disease and the activity of the lesions.
MHC class II molecules were expressed on Microglia and Macrophages, but not on Astrocytes. These data indicate that in MS lesions all cells of the Central Nervous System are potential targets for Class I MHC restricted cytotoxic T-Cells.
Neuronal Expression Of CD22: Novel Mechanism For inhibiting Microglial ProInflammatory Cytokine Production
Mott RT, Ait-Ghezala G, Town T, Mori T, Vendrame M, Zeng J, Ehrhart J, Mullan M, Tan J
Glia 2004 May;46(4):369-79
Duke University Medical Center, Department of Pathology, Durham, North Carolina, USA
Although considered an Immunologically privileged site, the Central Nervous System (CNS) can display significant inflammatory responses, which may play a pathogenic role in a number of Neurological Diseases.
Microglia appear to be particularly important for initiating and sustaining CNS inflammation.
These cells exist in a quiescent form in the normal CNS, but acquire Macrophage-like properties (including active Phagocytosis, upregulation of proteins necessary for Antigen Presentation, and production of ProInflammatory Cytokines) after stimulation with inflammatory substances such as LipoPolySaccharide (LPS).
Recent studies have focused on elucidating the role of Neurons in the regulation of Microglial inflammatory responses.
In the present study, we demonstrate, using Neuron-Microglial cocultures, that Neurons are capable of inhibiting LPS-induced Tumor Necrosis Factor-alpha (TNF-alpha) production by Microglia.
This inhibition appears to be dependent on secretion of substances at Axon terminals, as treatment with the PreSynaptic Calcium Channel blocker omega-Conotoxin abolishes this inhibitory effect.
Moreover, we show that conditioned medium from Neuronal cultures similarly inhibits Microglial TNF-alpha production, which provides additional evidence that Neurons secrete inhibitory substances.
We previously demonstrated that the transmembrane protein-Tyrosine Phosphatase CD45 plays an important role in negatively regulating Microglial activation.
The recent characterization of CD22 as an endogenous Ligand of this Receptor led us to investigate whether Neurons express this protein.
Indeed, we were able to demonstrate CD22 mRNA and protein expression in cultured Neurons and mouse Brain, using reverse transcriptase-polymerase chain reaction and AntiBody-based techniques.
Furthermore, we show that Neurons secrete CD22, which functions as an inhibitor of Microglial ProInflammatory Cytokine production.
Copyright 2004 Wiley-Liss, Inc.
The Role Of Macrophage/Microglia And Astrocytes In The Pathogenesis Of Three Neurologic Disorders: HIV-Associated Dementia, Alzheimer Disease, And Multiple Sclerosis
Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M, Eisdorfer C
J Neurol Sci 2002 Oct 15;202(1-2):13-23
Louisiana State University School of Medicine, Department of Neurology, Shreveport, LA 71130, USA
Macrophage/Microglia (M phi) are the principal Immune Cells in the Central Nervous System (CNS) concomitant with Inflammatory Brain Disease and play a significant role in the host defense against invading microorganisms.
Astrocytes, as a significant component of the Blood-Brain Barrier, behave as one of the Immune Effector Cells in the CNS as well.
However, both cell types may play a dual role, amplifying the effects of inflammation and mediating cellular damage as well as protecting the CNS.
Interactions of the Immune System, M phi, and Astrocytes result in altered production of NeuroToxins and NeuroTrophins by these cells.
These effects alter the Neuronal structure and function during pathogenesis of HIV-1-Associated Dementia (HAD), Alzheimer Disease (AD), and Multiple Sclerosis (MS).
HAD primarily involves SubCortical Gray Matter, and both HAD and MS affect SubCortical White Matter. AD is a Cortical Disease.
The process of M phi and Astrocytes activation leading to NeuroToxicity share similarities among the three diseases.
Human Immunodeficiency Virus (HIV)-1-infected M phi are involved in the pathogenesis of HAD and produce toxic molecules including Cytokines, Chemokines, and Nitric Oxide (NO).
In AD, M phi produce these molecules and are activated by beta-Amyloid Proteins and related OligoPeptides.
DeMyelination in MS involves M phi that become lipid laden, spurred by several possible Antigens.
In these three diseases, Cytokine/Chemokine communications between M phi and Astrocytes occur and are involved in the balance of protective and destructive actions by these cells.
This review describes the role of M phi and Astrocytes in the pathogenesis of these three Progressive Neurological Diseases, examining both beneficent and deleterious effects in each disease.
Copyright 2002 Elsevier Science B.V.
Regulation And Function Of Class II Major Histocompatibility Complex, CD40, And B7 Expression In Macrophages And Microglia: Implications In Neurological Diseases
O'Keefe GM, Nguyen VT, Benveniste EN
J NeuroVirol 2002 Dec;8(6):496-512
University of Alabama at Birmingham, Department of Cell Biology, Birmingham, Alabama, USA
The ability of Microglia, the Brain's resident Macrophage, to present Antigen through the Class II Major Histocompatibility Complex (MHC) to T-Cells allows these normally quiescent cells to play a critical role in shaping the outcome of many Neurological Diseases.
The expression of Class II MHC Antigens and the CoStimulatory molecules CD40 and B7 on Microglia and infiltrating Macrophages is regulated through a complex network of Cytokines in the inflamed Brain.
In this review, we describe the molecular mechanisms underlying Class II MHC, CD40 and B7 regulation in Microglia and Macrophages. Our focus is on the cis-elements in the promoters of their genes and the transcription factors activated by Cytokines that bind them.
The functional implications of aberrant Class II MHC, CD40 and B7 expression by Microglia and Macrophages as related to the diseases of Multiple Sclerosis and Alzheimer's Disease are discussed.