Microglia in the pathogenesis of MS

[frodo]

Microglia in the pathogenesis of MS

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499932/



We postulate that the immune reaction initiates in the CNS and immune cells (including T cells/B cell) infiltrate into the CNS as a result.

An unknown causative agent sets off a local inflammatory reaction, after which activated microglia are stimulated by the microenvironment to differentiate into many subgroups that then serve as APCs, phagocytes, and immune effector cells to activate T cells. Activated T cells can then cross the blood–brain barrier and result in a peripheral immune response.

Subsequently, activated T cells, B cells, and macrophages migrate from the periphery into the CNS, which exacerbates the inflammation or leads to relapse.

This hypothesis could explain some phenomena in MS patients. First, the APCs (microglia and macrophages) originate in the CNS, are recognized by CNS-resident cells, and remain localized within the CNS, which could explain why MS patients experience no peripheral complications, such as autoimmune nephritis and arthritis. Second, the inflammatory cascade occurs entirely within the CNS, which could explain the insufficiency or the absence of lymphocyte recruitment into the CNS after the initial relapsing phase of MS

Also interesting:

Microglia show a clear region-specific profile, indicated by higher expression of type-I interferon genes in GM and higher expression of NF-κB pathway genes in WM. Transcriptional changes in MS microglia also differ between GM and WM. MS WM microglia show increased lipid metabolism gene expression, which relates to MS pathology since active MS lesion-derived microglial nuclei show similar altered gene expression (https://www.ncbi.nlm.nih.gov/pubmed/30867424).

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.. Second, the inflammatory cascade occurs entirely within the CNS, which could explain the insufficiency or the absence of lymphocyte recruitment into the CNS after the initial relapsing phase of MS

December 7, 2017
Department of neuroradiologie, Heidelberg University Hospital, Heidelberg, NěmeckoIn the Pipeline-Multiple Sclerosis: Neurographic MRI Reveals Peripheral Nerve Lesions in MS Patients
https://journals.lww.com/neurotodayonli ... hic.6.aspx

.. Current opinion is that pathological changes in MS are restricted to the central nervous system (CNS) and cranial nerves, but the new proof-of-concept study may offer new insights into the pathophysiology of the disease and help guide new treatment options, said lead author Jennifer Kollmer, MD, a neuroradiologist at Heidelberg University Hospital..

[NHE]

December 7, 2017
Department of neuroradiologie, Heidelberg University Hospital, Heidelberg, NěmeckoIn the Pipeline-Multiple Sclerosis: Neurographic MRI Reveals Peripheral Nerve Lesions in MS Patients
https://journals.lww.com/neurotodayonli ... hic.6.aspx

.. Current opinion is that pathological changes in MS are restricted to the central nervous system (CNS) and cranial nerves, but the new proof-of-concept study may offer new insights into the pathophysiology of the disease and help guide new treatment options, said lead author Jennifer Kollmer, MD, a neuroradiologist at Heidelberg University Hospital..

It sounds like they may not be exactly sure of what the significance is of the lesions they're detecting.

Dr. Jacobs added that it is also worth noting that the healthy controls had quite a few lesions, implying that MRN may pick up very subtle disturbances of peripheral nerve myelin which don't have any functional importance.

[frodo]

It looks like microglia is the root of all evil. Microglia activation is the first step in the so-called "preactive lesions" (with some doubts, see below), it appears in the "normal appearing white matter" and also in the cortical lesions.

Why that happens is unknown, but microglia activation is something that happens when a virus or antigen is present. Anyway it could be just a metabolic problem, because fingolimod prevents microglia activation without bad consequences.

There is a review about Microglia activation here:

Microglial Phenotypes and Functions in Multiple Sclerosis

http://perspectivesinmedicine.cshlp.org ... 28993.full

Some excerpts:

"In line with this concept, preactive lesions have been described in MS, which are defined by clusters of activated microglia in the white matter of MS patients, which develop without demyelination and peripheral cell infiltration (van Horssen et al. 2012), and thus may represent the early stage of inflammatory lesion (van Noort et al. 2011). However, these “preactive” lesions have been described in progressive MS, are very frequent and widespread, and it is therefore highly unlikely that such lesions develop into classical active MS plaques. In addition, they are poorly defined and may also reflect areas of diffuse microglia activation in the normal-appearing white matter of MS patients as well as areas of secondary Wallerian degeneration or even remyelination"

"From all these studies, it is clear that active demyelination and neurodegeneration is associated with microglia activation. Whether this microglia activation is the primary trigger of lesion formation, whether they are activated by T lymphocytes or B cells, or they are secondary to tissue injury mediated by soluble factors produced by cells of the adaptive immune system is currently unresolved. "

"A proof-of-principle, that inhibition of microglia activation has a beneficial effect on MS, has recently been obtained in a trial using minocycline. This drug, which has been shown to target microglia activation and has beneficial effects in several different experimental models of inflammation and neurodegeneration, reduced the conversion of clinically isolated syndrome (CIS) into definite MS in MS patients and reduced clinically or radiologically identified activity of the disease"

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2018 Jul 3
Neuroscience Laboratory, Laval University, Quebec, QC, Canad
mCSF-Induced Microglial Activation Prevents Myelin Loss and Promotes Its Repair in a Mouse Model of Multiple Sclerosis
https://www.ncbi.nlm.nih.gov/pubmed/30018535

Abstract
A pathological hallmark of multiple sclerosis (MS) is myelin loss in brain white matter accompanied by compromised remyelination. Demyelinated lesions are deeply associated with oligodendrocyte apoptosis and a robust inflammatory response. Although various studies point towards a noxious role of inflammation in MS, others emphasize a positive role for the innate immune cells in disease progression. A cytokine well-known to stimulate cell survival, proliferation and differentiation of myeloid cells, macrophage colony-stimulating factor (mCSF), was administered to mice during a 5 week-long cuprizone diet. Treated mice exhibited reduced myelin loss during the demyelination phase, together with an increased number of microglia and oligodendrocyte precursor cells in lesion sites. Tamoxifen-induced conditional deletion of the mCSF receptor in microglia from cuprizone-fed mice caused aberrant myelin debris accumulation in the corpus callosum and reduced microglial phagocytic response. mCSF therefore plays a key role in stimulating myelin clearance by the brain innate immune cells, which is a prerequisite for proper remyelination and myelin repair processes.

full https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037698/

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2018 Aug 9
Department of Radiology/Nuclear Medicine, Weill Cornell Medicine, New York, New York City
Comparison of two different methods of image analysis for the assessment of microglial activation in patients with multiple sclerosis using (R)-[N-methyl-carbon-11]PK11195
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084893/

Abstract
Chronic active multiple sclerosis (MS) lesions have a rim of activated microglia/macrophages (m/M) leading to ongoing tissue damage, and thus represent a potential treatment target. Activation of this innate immune response in MS has been visualized and quantified using PET imaging with [11C]-(R)-PK11195 (PK). Accurate identification of m/M activation in chronic MS lesions requires the sensitivity to detect lower levels of activity within a small tissue volume. We assessed the ability of kinetic modeling of PK PET data to detect m/M activity in different central nervous system (CNS) tissue regions of varying sizes and in chronic MS lesions. Ten patients with MS underwent a single brain MRI and two PK PET scans 2 hours apart. Volume of interest (VOI) masks were generated for the white matter (WM), cortical gray matter (CGM), and thalamus (TH). The distribution volume (VT) was calculated with the Logan graphical method (LGM-VT) utilizing an image-derived input function (IDIF). The binding potential (BPND) was calculated with the reference Logan graphical method (RLGM) utilizing a supervised clustering algorithm (SuperPK) to determine the non-specific binding region. Masks of varying volume were created in the CNS to assess the impact of region size on the various metrics among high and low uptake regions. Chronic MS lesions were also evaluated and individual lesion masks were generated. The highest PK uptake occurred the TH and lowest within the WM, as demonstrated by the mean time activity curves. In the TH, both reference and IDIF based methods resulted in estimates that did not significantly depend on VOI size. However, in the WM, the test-retest reliability of BPND was significantly lower in the smallest VOI, compared to the estimates of LGM-VT. These observations were consistent for all chronic MS lesions examined. In this study, we demonstrate that BPND and LGM-VT are both reliable for quantifying m/M activation in regions of high uptake, however with blood input function LGM-VT is preferred to assess longitudinal m/M activation in regions of relatively low uptake, such as chronic MS lesions.

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2018 Sep 8
Università degli Studi di Milano, via Balzaretti, Milan, Italy
How to reprogram microglia toward beneficial functions
https://www.ncbi.nlm.nih.gov/pubmed/30195261

Abstract
Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro-regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders.

[NHE]

2018 Sep 8
Università degli Studi di Milano, via Balzaretti, Milan, Italy
How to reprogram microglia toward beneficial functions
https://www.ncbi.nlm.nih.gov/pubmed/30195261

Free full text at...

https://onlinelibrary.wiley.com/doi/pdf ... glia.23484

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2018 Sep 12
Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
Early P2X7R-dependent activation of microglia during the asymptomatic phase of EAE
https://www.ncbi.nlm.nih.gov/pubmed/30209761

Abstract
Microglia-mediated neuroinflammation accompanies many central nervous system (CNS) diseases, including multiple sclerosis (MS), and is strongly dependent on the purinergic P2X7 receptor. The nature of the inflammatory response in MS is studied for decades indicating, that proinflammatory microgliosis is involved in advanced stages of MS and is associated with active tissue damage and neurological dysfunctions. Evidence on the role of microgliosis in initial stages of the disease is scarce. Thus, in the present study, we investigated the time course of microglial activation in rat brain subjected to experimental autoimmune encephalomyelitis (EAE) which is the animal model of MS. We show that activation of microglia occurs in brains of immunized rats at a very early stage of EAE, well before the development of neurological symptoms of the disease. Enhanced immunoreactivity of microglia/macrophage-specific protein Iba-1, together with morphological features of microgliosis, was identified beginning at day 4 post immunization. Concomitantly, microglial expression of P2X7R was also examined. Moreover, our results reveal that administration of Brilliant Blue G, an antagonist of P2X7R, delays the onset of the disease and partially inhibits development of neurological symptoms in EAE rats. Blockage of P2X7R significantly reduces activation of microglia as confirmed by decreased Iba-1 immunoreactivity and suppresses neuroinflammation in EAE rat brains, as indicated by decreased protein levels of investigated proinflammatory cytokines: IL-1β, IL-6 and TNF-α. Our results indicate that microglia are involved in inducing neuroinflammation at a very early stage of MS/EAE via a P2X7R-dependent mechanism.

wiki P2RX7 https://en.wikipedia.org/wiki/P2RX7
.. The P2X7 receptor current can be blocked by zinc, calcium, magnesium, and copper

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2018 Nov 21
Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge
Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes
https://www.ncbi.nlm.nih.gov/pubmed/30471926

Abstract
Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. Here, we analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers. The greatest microglial heterogeneity was found at young ages; however, several states-including chemokine-enriched inflammatory microglia-persisted throughout the lifespan or increased in the aged brain. Multiple reactive microglial subtypes were also found following demyelinating injury in mice, at least one of which was also found in human multiple sclerosis lesions. These distinct microglia signatures can be used to better understand microglia function and to identify and manipulate specific subpopulations in health and disease.

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2019 Mar 22
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
Targeting Microglia and Macrophages: A Potential Treatment Strategy for Multiple Sclerosis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438858/

Abstract
Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS). The early stage is characterized by relapses and the later stage, by progressive disability. Results from experimental and clinical investigations have demonstrated that microglia and macrophages play a key part in the disease course. These cells actively initiate immune infiltration and the demyelination cascade during the early phase of the disease; however, they promote remyelination and alleviate disease in later stages. This review aims to provide a comprehensive overview of the existing knowledge regarding the neuromodulatory function of macrophages and microglia in the healthy and injured CNS, and it discusses the feasibility of harnessing microglia and macrophage physiology to treat MS. The review encourages further investigations into macrophage-targeted therapy, as well as macrophage-based drug delivery, for realizing efficient treatment strategies for MS.

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2019 Apr 17
Department of Pathology and Immunology, Washington University in St. Louis, St. Louis
Fifty Shades of Microglia
https://www.ncbi.nlm.nih.gov/pubmed/31005331

Abstract
In a recent study, Masuda and colleagues (Nature 2019;566:388-392) used single-cell RNA-sequencing (scRNA-seq) to profile microglia across different anatomical compartments, developmental stages, and types of brain pathology in mice. Moreover, the authors performed a novel transcriptomic characterization of microglia from multiple sclerosis patients and identified phenotypically conserved microglial subsets between species. These findings, together with seminal prior results from various groups, provide valuable insights into the spatiotemporal heterogeneity of microglia during brain development and disease.

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2018 May
Johns Hopkins Hospital and Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore
Much, if not all, of the cortical damage in MS can be attributed to the microglial cell – Yes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029145/

2018 May 14
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland
Much, if not all, of the cortical damage in MS can be attributed to the microglia cells - NO https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995597/

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2019 Oct 11
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
The Role of Neuronal Factors in the Epigenetic Reprogramming of Microglia in the Normal and Diseased Central Nervous System.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798237/

Abstract
Twenty years ago, the scientific community exhibited relatively little interest in the study of microglial cells. However, recent technical and conceptual advances in this field have greatly increased interest in the basic biology of these cells within various neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and traumatic brain/spinal cord injuries. The main functions of these cells in the normal central nervous system (CNS) remain poorly understood, despite considerable elucidation of their roles in pathological conditions. Microglia populate the brain before birth and remain in close lifelong contact with CNS-resident cells under the influence of the local microenvironment. Within the CNS parenchyma, microglia actively interact with two main cell types, astrocytes and neurons, which produce many factors that affect microglia phenotypes in the normal CNS and during neuroinflammation. These factors include interleukin (IL)-34, macrophage colony-stimulating factor, transforming growth factor-β, and IL-4, which promote microglial expansion, survival, and differentiation to an anti-inflammatory phenotype in the normal CNS. Under inflammatory conditions, however, astrocytes produce several pro-inflammatory factors that contribute to microglial activation. The interactions of microglia with neurons in the normal and diseased CNS are especially intriguing. Microglia are known to interact actively with neurons by facilitating axonal pruning during development, while neurons provide specific factors that alter microglial phenotypes and functions. This review focuses mainly on the roles of soluble neuronal factors that affect microglial phenotypes and functions and the possible involvement of these factors in the pathology of neurodegenerative diseases.

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2019 Nov 12
Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
LXW7 attenuates inflammation via suppressing Akt/nuclear factor kappa B and mitogen-activated protein kinases signaling pathways in lipopolysaccharide-stimulated BV2 microglial cells.
https://www.ncbi.nlm.nih.gov/pubmed/31732449

Abstract

Microglia activation is closely linked to ischemia, various chronic neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis), and many other central nervous system diseases. Accumulating evidence suggests that depressing the microglial inflammatory response could be an effective treatment for inflammatory disorders. The integrin αvβ3 inhibitor LXW7 has a neuroprotective effect; however, its anti-inflammatory effects and underlying mechanism remain unclear. Thus, we examined whether LXW7 would inhibit inflammatory cytokines and mediators, and we evaluated the potential mechanisms of its neuroprotective effects. Nitrite analysis revealed LXW7 reduced the nitric oxide (NO) level. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) suggested that LXW7 suppressed the expression of proinflammatory genes for tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and anti-inflammatory gene interleukin 10 (IL-10) at the messenger ribonucleic acid level. Enzyme-linked immunosorbent assay results demonstrated that LXW7 treatment reduced the expression of prostaglandin E2 (PGE2), TNF-α, IL-1β and IL-10 at the protein level. Western blotting was conducted to confirm the upregulation of inflammatory factors, including iNOS and COX-2 at the protein level. LXW7 inhibited major genes in the Akt/NF-κB and c-Jun NH2-terminal kinase/ mitogen-activated protein kinases (JNK/MAPK) signaling pathways. Immunofluorescence revealed that LXW7 inhibited the nuclear translocation of nuclear factor kappa B (NF-κB). Thus, LXW7 effectively alleviated LPS-induced inflammatory damage and had neuroprotective effects. The anti-inflammatory effects of LXW7 may be associated with the inhibition of microglial activation via Akt/NF-κB and JNK/MAPK signaling pathways by blocking integrin αvβ3 receptor. The present study's findings suggest that LXW7 has a substantial therapeutic potential for treating inflammatory and neurodegenerative diseases.