Microglia: Agents of the CNS Pro-Inflammatory Response

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Abstract

The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.

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Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

Olivier Micheau, Jurg Tschopp (2003)

Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.

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The Microglial Sensome Revealed by Direct RNA Sequencing

Suzanne E Hickman, Nathan D. Kingery, Toshiro K Ohsumi … (2013)

Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluorescent dual in-situ hybridization, unbiased proteomic analysis and quantitative PCR. We report here that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we term the “sensome”. With aging, sensome transcripts for endogenous ligand recognition are downregulated, whereas those involved in microbe recognition and host defense are upregulated. In addition, aging is associated with an overall increase in expression of microglial genes involved in neuroprotection.

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Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.

T R Mosmann, H Cherwinski, M Bond … (1986)

A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.

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Journal

Journal ID (nlm-ta): Cells

Journal ID (iso-abbrev): Cells

Journal ID (publisher-id): cells

Title: Cells

Publisher: MDPI

ISSN (Electronic): 2073-4409

Publication date (Electronic): 17 July 2020

Publication date Collection: July 2020

Volume: 9

Issue: 7

Electronic Location Identifier: 1717

Affiliations

[1 ]Institute of Biomedicine of Seville (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/University of Seville, 41012 Seville, Spain; rodriguez@ 123456us.es (J.A.R.-G.); ajherrera@ 123456us.es (A.J.H.); anaespinosa@ 123456us.es (A.M.E.-O.); jlvenero@ 123456us.es (J.L.V.)

[2 ]Department of Medical Physiology and Biophysics, Faculty of Medicine, University of Seville, 41009 Sevilla, Spain

[3 ]Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain; ekavanagh@ 123456us.es

[4 ]Institute of Environmental Medicine, Toxicology Unit, Karolinska Institute, 17177 Stockholm, Sweden; pinelopi.vlachos@ 123456ki.se (P.E.-V.); bertrand.joseph@ 123456us.es (B.J.)

[5 ]Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala University, 751 23 Uppsala, Sweden; mikael.engskog@ 123456ilk.uu.se

[6 ]Division of Brain Sciences, The John Fulcher Molecular Neuro-Oncology Laboratory, Imperial College London, London W12 ONN, UK; n.hajji@ 123456imperial.ac.uk

Author notes

[* ]Correspondence: maburguillos@ 123456us.es

[†]

Equal contributions.

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José L. Venero https://orcid.org/0000-0003-1137-8706

Article

Publisher ID: cells-09-01717

DOI: 10.3390/cells9071717

PMC ID: 7407646

PubMed ID: 32709045

SO-VID: 4b3ada41-ecae-4312-b006-7a96e854ce47

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Microglia: Agents of the CNS Pro-Inflammatory Response

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Biomarkers for Inflammatory Lung Disease

Most cited references 241

Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

The Microglial Sensome Revealed by Direct RNA Sequencing

Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.

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