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      Microglial regional heterogeneity and its role in the brain

      review-article
      Author(s): 1 , 2 , 1 , 3 ,
      Publication date (Electronic):
      Journal: Molecular Psychiatry
      Publisher: Nature Publishing Group UK
      Keywords: Neuroscience, Psychiatric disorders

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          Abstract

          Microglia have been recently shown to manifest a very interesting phenotypical heterogeneity across different regions in the mammalian central nervous system (CNS). However, the underlying mechanism and functional meaning of this phenomenon are currently unclear. Baseline diversities of adult microglia in their cell number, cellular and subcellular structures, molecular signature as well as relevant functions have been discovered. But recent transcriptomic studies using bulk RNAseq and single-cell RNAseq have produced conflicting results on region-specific signatures of microglia. It is highly speculative whether such spatial heterogeneity contributes to varying sensitivities of individual microglia to the same physiological and pathological signals in different CNS regions, and hence underlie their functional relevance for CNS disease development. This review aims to thoroughly summarize up-to-date knowledge on this specific topic and provide some insights on the potential underlying mechanisms, starting from microgliogenesis. Understanding regional heterogeneity of microglia in the context of their diverse neighboring neurons and other glia may provide an important clue for future development of innovative therapies for neuropsychiatric disorders.

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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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            Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution

            Hansruedi Mathys, Chinnakkaruppan Adaikkan, Fan Gao … (2017)
            SUMMARY Microglia, the tissue-resident macrophages in the brain, are damage sensors that react to nearly any perturbation, including neurodegenerative diseases such as Alzheimer’s disease (AD). Here, using single-cell RNA sequencing, we determined the transcriptome of more than 1,600 individual microglia cells isolated from the hippocampus of a mouse model of severe neurodegeneration with AD-like phenotypes and of control mice at multiple time points during progression of neurodegeneration. In this neurodegeneration model, we discovered two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively. Furthermore, our work identified previously unobserved heterogeneity in the response of microglia to neurodegeneration, discovered disease stage-specific microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration, and uncovered the underlying transcriptional programs.
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              Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials.

              Ole Köhler, Michael Benros, Merete Nordentoft … (2014)
              Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents. To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions. Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles. Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression. Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated. Depression scores after treatment and adverse effects. Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n=4,258) and 4 investigated cytokine inhibitors (n=2,004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, -0.34; 95% CI, -0.57 to -0.11; I2=90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, -0.54; 95% CI, -1.08 to -0.01; I2=68%) and depressive symptoms (SMD, -0.27; 95% CI, -0.53 to -0.01; I2=68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, -0.29; 95% CI, -0.49 to -0.08; I2=73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2=0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2=0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity. Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.
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                Author and article information

                Contributors
                Li Tian:
                ORCID: http://orcid.org/0000-0003-0222-7076
                +372-737-4418 , li.tian@ut.ee
                Journal
                Journal ID (nlm-ta): Mol Psychiatry
                Journal ID (iso-abbrev): Mol. Psychiatry
                Title: Molecular Psychiatry
                Publisher: Nature Publishing Group UK (London )
                ISSN (Print): 1359-4184
                ISSN (Electronic): 1476-5578
                Publication date (Electronic): 26 November 2019
                Publication date PMC-release: 26 November 2019
                Publication date (Print): 2020
                Volume: 25
                Issue: 2
                Pages: 351-367
                Affiliations
                [1 ]ISNI 0000 0001 2256 9319, GRID grid.11135.37, Psychiatry Research Centre, Beijing Huilongguan Hospital, , Peking University Health Science Center, ; Beijing, China
                [2 ]GRID grid.459434.b, Children’s Hospital of Capital Institute of Pediatrics, ; Beijing, China
                [3 ]ISNI 0000 0001 0943 7661, GRID grid.10939.32, Institute of Biomedicine and Translational Medicine, Department of Physiology, Faculty of Medicine, , University of Tartu, ; Tartu, Estonia
                Author information
                http://orcid.org/0000-0003-0222-7076
                Article
                Publisher ID: 609
                DOI: 10.1038/s41380-019-0609-8
                PMC ID: 6974435
                PubMed ID: 31772305
                SO-VID: 4a016617-4b57-4986-b092-63e177ed4204
                Copyright © © The Author(s) 2019
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 7 August 2019
                Date revision received : 7 November 2019
                Date accepted : 13 November 2019
                Categories
                Subject: Review Article
                Custom metadata
                issue-copyright-statement © Springer Nature Limited 2020

                ScienceOpen disciplines: Molecular medicine
                Keywords: neuroscience,psychiatric disorders
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: neuroscience, psychiatric disorders

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