Microglia in the pathogenesis of MS

A forum to discuss research on the origins of MS and its development.
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Petr75
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Re: Microglia in the pathogenesis of MS

Post by Petr75 » Wed Nov 27, 2019 8:46 am

2019 Nov 15
Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown
Heterogeneity of microglia and their differential roles in white matter pathology.
https://www.ncbi.nlm.nih.gov/pubmed/31733036

Abstract

Microglia are resident immune cells that play multiple roles in central nervous system (CNS) development and disease. Although the classical concept of microglia/macrophage activation is based on a biphasic beneficial-versus-deleterious polarization, growing evidence now suggests a much more heterogenous profile of microglial activation that underlie their complex roles in the CNS. To date, the majority of data are focused on microglia in gray matter. However, demyelination is a prominent pathologic finding in a wide range of diseases including multiple sclerosis, Alzheimer's disease, and vascular cognitive impairment and dementia. In this mini-review, we discuss newly discovered functional subsets of microglia that contribute to white matter response in CNS disease onset and progression. Microglia show different molecular patterns and morphologies depending on disease type and brain region, especially in white matter. Moreover, in later stages of disease, microglia demonstrate unconventional immuno-regulatory activities such as increased phagocytosis of myelin debris and secretion of trophic factors that stimulate oligodendrocyte lineage cells to facilitate remyelination and disease resolution. Further investigations of these multiple microglia subsets may lead to novel therapeutic approaches to treat white matter pathology in CNS injury and disease.

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Petr75
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Re: Microglia in the pathogenesis of MS

Post by Petr75 » Thu May 28, 2020 10:46 am

2020 Apr 29
Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, Germany
Regulation of Microglial Functions by Purinergic Mechanisms in the Healthy and Diseased CNS
https://pubmed.ncbi.nlm.nih.gov/32365642/

Abstract

Microglial cells, the resident macrophages of the central nervous system (CNS), exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell-damaging factors, they get transformed into an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen species, and the excytotoxic ATP and glutamate. In addition, they engulf pathogenic bacteria or cell debris and phagocytose them. However, already resting/surveying microglia have a number of important physiological functions in the CNS; for example, they shield small disruptions of the blood-brain barrier by their processes, dynamically interact with synaptic structures, and clear surplus synapses during development. In neurodegenerative illnesses, they aggravate the original disease by a microglia-based compulsory neuroinflammatory reaction. Therefore, the blockade of this reaction improves the outcome of Alzheimer's Disease, Parkinson's Disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. The function of microglia is regulated by a whole array of purinergic receptors classified as P2Y12, P2Y6, P2Y4, P2X4, P2X7, A2A, and A3, as targets of endogenous ATP, ADP, or adenosine. ATP is sequentially degraded by the ecto-nucleotidases and 5'-nucleotidase enzymes to the almost inactive inosine as an end product. The appropriate selective agonists/antagonists for purinergic receptors as well as the respective enzyme inhibitors may profoundly interfere with microglial functions and reconstitute the homeostasis of the CNS disturbed by neuroinflammation.

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Petr75
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Re: Microglia in the pathogenesis of MS

Post by Petr75 » Sat Jun 13, 2020 9:37 am

2020 Apr 28
School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
Lipid and Lipoprotein Metabolism in Microglia
https://pubmed.ncbi.nlm.nih.gov/32411016/

Abstract

Microglia, once viewed as static bystanders with limited homeostatic functions, are now considered key players in the development of neuroinflammatory and neurodegenerative diseases. Microglial activation is a salient feature of neuroinflammation involving a dynamic process that generates multitudinous microglial phenotypes that can respond to a variety of situational cues in the central nervous system. Recently, a flurry of single cell RNA-sequencing studies have defined microglial phenotypes in unprecedented detail, and have highlighted robust changes in the expression of genes involved in lipid and lipoprotein metabolism. Increased expression of genes such as Apolipoprotein E (ApoE), Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and Lipoprotein Lipase (LPL) in microglia during development, damage, and disease, suggest that increased lipid metabolism is needed to fuel protective cellular functions such as phagocytosis. This review describes our current understanding of lipid and lipoprotein metabolism in microglia, and highlights microglial lipid metabolism as a modifiable target for the treatment of neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis.

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NHE
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Re: Microglia in the pathogenesis of MS

Post by NHE » Sat Jun 13, 2020 4:30 pm

Petr75 wrote:
Sat Jun 13, 2020 9:37 am
2020 Apr 28
School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
Lipid and Lipoprotein Metabolism in Microglia
https://pubmed.ncbi.nlm.nih.gov/32411016/

Free full text. https://www.ncbi.nlm.nih.gov/pmc/articl ... -00393.pdf

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Petr75
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Re: Microglia in the pathogenesis of MS

Post by Petr75 » Sun Sep 20, 2020 4:47 am

2020 Aug 20
Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Italy
Mitochondrial damage-associated molecular patterns stimulate reactive oxygen species production in human microglia
https://pubmed.ncbi.nlm.nih.gov/32828963/

Abstract

Microglia are the resident innate immune cells of the central nervous system and exert functions of host defense and maintenance of normal tissue homeostasis, along with support of neuronal processes in the healthy brain. Chronic and dysregulated microglial cell activation has increasingly been linked to the status of neuroinflammation underlying many neurodegenerative diseases, including multiple sclerosis (MS). However, the stimulus (or stimuli) and mechanisms by which microglial activation is initiated and maintained MS are still debated. The purpose of our research was to investigate whether the endogenous mitochondrial (mt)-derived damage-associated molecular patterns (MTDs) mtDNA, N-formyl peptides and cardiolipin (CL) contribute to these phenomena. We characterized the effects of the abovementioned MTDs on microglia activation in vitro (i.e. using HMC3 cells) by evaluating the expression of gene coding for proteins involved in their binding and coupled to downstream signaling pathways, the up-regulation of markers of activation on the cell surface and the production of pro-inflammatory cytokines and reactive oxygen species. At the transcriptional level, significant variations in the mRNA relative expression of five of eleven selected genes were observed in response to stimulation. No changes in activation of antigenic profile or functional properties of HMC3 cells were observed; there was no up-regulation of HLA-DR expression or increased secretion of tumor necrosis factor-α and interleukin-6. However, after stimulation with mtDNA and CL, an increase in cellular oxidative stress, but not in the mt ROS O2-, compared to control cells, were observed. There were no effects on cell viability. Overall, our data suggest that MTDs could cause a failure in microglial activation toward a pro-inflammatory phenotype, possibly triggering an endogenous regulatory mechanism for the resolution of neuroinflammation. This could open a door for the development of drugs selectively targeting microglia and modulating its functionality to treat MS and/or other neurodegenerative conditions in which MTDs have a pathogenic relevance.

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