Astrocytes are a sub-type of neuroglia responsible for homoeostasis and defence of the nervous system. Pathological reactions of neuroglial cells in various neurological disorders have been identified and characterised in the end of the 19th century; in particular hypertrophy of astrocytes was recognised as a frequent morbid change accompanying diseases of the central nervous system (CNS).This work was supported by grants of the National Key R&D Programme of China (2019YFC1709101) and the Project First-Class Disciplines Development of Chengdu University of Traditional Chinese Medicine (CZYHW1901) awarded in order to build up the “International Collaborative Centre on Big Science Plan for Purinergic Signalling”, and the Science and Technology Programme of Sichuan Province, China (2019YFH0108). The stay and work of PI in Chengdu was supported by a grant from the State Administration of Foreign Experts Affairs (G20190236012). A.S. and Y.T. are supported by RFBR grant 21-54-53018 for the NSFC-RFBR projec

Illes, Peter

Semyanov, Alexey

Tang, Yong

Verkhratsky, Alexei

Signal Transduction and Targeted Therapy

English

The University of Manchester - Institutional Repository

The anti-inflammatory astrocyte revealed: the role of the microbiome in shaping brain defences

Archivo Digital para la Docencia y la Investigación

RESEARCH HIGHLIGHT OPENThe anti-inflammatory astrocyte revealed: the role of themicrobiome in shaping brain defencesAlexei Verkhratsky 1,2,3,4, Peter Illes4,5, Yong Tang 4 and Alexey Semyanov 3,6,7Signal Transduction and Targeted Therapy           (2021) 6:150 ; https://doi.org/10.1038/s41392-021-00577-5The paper, published recently in Nature by the group of FranciscoQuintana,1 describes the anti-inflammatory astrocytes, activity ofwhich is tuned by the microbiotome and meningeal natural killer(NK) cells.Astrocytes are a sub-type of neuroglia responsible for homo-eostasis and defence of the nervous system. Pathological reactionsof neuroglial cells in various neurological disorders have beenidentified and characterised in the end of the 19th century; inparticular hypertrophy of astrocytes was recognised as a frequentmorbid change accompanying diseases of the central nervoussystem (CNS). Subsequently, hyperplasia and proliferation ofastrocytes in response to polyetiological insults to the nervoustissue were formalised in a concept of reactive astrogliosis, whichwas considered to be a universal sign of neuropathology, a kind ofstereotypic response that provided “splint” (as it was called byWilder Penfield) to the nervous tissue and filled the spaces left bydisintegrating neurons; the ultimate outcome of astrogliosis was aformation of a glial scar.2 This view has dominated neurologicalthoughts for almost a century; however, recent two decades led toa fundamental revision of principles of astrogliopathology.3,4 First,it has been found that various diseases including, for instance,neuropsychiatric disease or various leucomalacia are associatedwith or even driven by astroglial asthenia, atrophy or loss offunction. Second, it appeared that astrogliosis generates multiplereactive phenotypes, characterised by distinct gene expressionsignatures and functional outcomes3,5; reactive astrocytes oftenact as neuroprotectors but sometimes acquire deleteriousfeatures. Inhibition of reactive astrogliosis may either exacerbateor alleviate neurological outcome. Various reactive or asthenicastrocytic phenotypes may develop sequentially or simultaneouslyin different brain regions under the same pathological context.Otherwise, distinct pathological forms of astrocytes can be linkedto the disease stage, reflecting a high degree of pathologicalplasticity of astroglia. Astrocytic phenotypes and functions are alsoaffected by ageing, while the remodelling of astrocytes in the oldCNS can define the susceptibility of the nervous tissue to age-dependent neurodegenerative diseases.A previously unknown population of anti-inflammatory astro-cytes has been identified and characterised in the mouse brain bya combination of state-of-the-art techniques including single-cellRNA sequencing, high-throughput flow cytometry screening, andCRISPR–Cas9-based genetic manipulations.1 These specialisedastrocytes express the lysosomal associated protein 1 (LAMP1)and the death receptor activator TRAIL (encoded by Tnfsf10 gene),which both confer anti-inflammatory capabilities. The TRAILstands for tumour necrosis factor-related apoptosis-inducingligand; it belongs to the family of tumour necrosis factors, whichinstigate apoptosis through engaging death receptors and theirdownstream molecular cascades. The TRAIL-positive astrocyteslimit neuroinflammation in the experimental autoimmune ence-phalomyelitis (EAE) by initiating apoptotic death of infiltrating T-lymphocytes. Specific inactivation of TRAIL in astrocytes byinactivating the Tnfsf10 gene with Gfap-driven CRISPR–Cas9lentivirus aggravated EAE progression. The anti-inflammatoryTRAIL astrocytes seem to populate the spinal cord; they werenot identified in the cortex and cerebellum.The TRAIL-positive astrocytes are located close to meninges inmice and in humans; notably, their population is decreased intissues obtained from patients with diagnosed multiple sclerosis.The anti-inflammatory astrocytes are regulated by NK cellsresiding in meninges (Fig. 1); this regulation is mediated byinterferon-γ (IFN-γ). The NK cells are a part of innate tissueimmunity; these cells are large granular lymphocytes that areswiftly recruited in response to insults. The NK cells are cytolyticand secrete various cytokines; these cells are known to limitneuroinflammation, particularly in the context of multiplesclerosis. The NK cells are heterogeneous; a sub-population ofthem produce and secrete IFN-γ, a relatively small molecule (m.w.~16.8 kDa), which can diffuse through subarachnoid cerebrospinalfluid and reach astrocytic endfeet. When perceived by astrocyticreceptors, IFN-γ launches the yet unknown signalling cascade thatupregulates TRAIL expression and hence stimulates anti-inflammatory astrocyte defence. The state of NK cells is modulatedby systemic factors, and in particular, the production of IFN-γdepends on the gut flora. Depletion of the microbiome bytreatment with antibiotics resulted in a substantial decrease of theIFN-γ producing meningeal NK cells, although their total numberremains unchanged. Such a reduction translates into down-regulation of the anti-inflammatory astrocytes, thus presumablylimiting their protective potential.Identification of a specialised sub-type of anti-inflammatoryastrocytes further widens the repertoire or astrocytic capabilities torestrain diseases and adds a new dimension to our understanding ofastroglial plasticity in the healthy and diseased brain. The variationsReceived: 10 February 2021 Revised: 9 March 2021 Accepted: 15 March 20211Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; 2Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011Bilbao, Spain & Department of Neurosciences, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain; 3Sechenov First Moscow State Medical University, Moscow,Russia; 4School of Acupuncture and Tuina and International Collaborative Centre on Big Science Plan for Purinergic Signalling, Chengdu University of Traditional ChineseMedicine, Chengdu, China; 5Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany; 6Shemyakin-Ovchinnikov Institute of BioorganicChemistry, Russian Academy of Sciences, Moscow 117997, Russia and 7Faculty of Biology, Moscow State University, Moscow, RussiaCorrespondence: Alexei Verkhratsky (alexej.verkhratsky@manchester.ac.uk)www.nature.com/sigtransSignal Transduction and Targeted Therapy© The Author(s) 20211234567890();,:in the state of anti-inflammatory astrocytes are regulated by NKmeningeal cells, which, in their turn, are controlled by systemicimmunity and in particular, by the gut microbiome. The gut—NKcell—astrocytes axis clearly demonstrates the fundamental role ofsystemic factors in the regulation of various aspects of CNS function.The status of the gut–brain axis also defines the vulnerability of thenervous tissue to multiple diseases, as indeed deficiency in anti-inflammatory astrocytes may be directly linked to neuroinflamma-tory disorders such as multiple sclerosis. Manipulation with the gutmicrobiome may, therefore, represent a potentially powerfultherapeutic strategy. It also remains to be seen whether anti-inflammatory astrocytes operate only in the spinal cord or similarcells populate other brain parts; it is also imperative to discernmorphological and physiological peculiarities of these astrocytes.Conceptually, the state of neuroglia defines the brain vulner-ability to pathology. In this respect, all types of neuroglia seem towork in concert to keep the homoeostasis of the nervous tissueintact in the face of ongoing environmental challenges. Insults tothe brain similarly trigger a concerted response of all neuroglialcells aimed at resolution of pathology, regeneration and return tothe physiological homoeostatic state. Neuroglial failure at everystage facilitates neuropathology, whereas deficient defencepromotes the death of neural tissue. Neuroglia, therefore,represents a primary target for preventive medicine as manipula-tion with protective glial phenotypes may arrest or retardpathological evolution. The discovery of a new set of astroglianot only adds to astroglial heterogeneity and plasticity but alsohints at many more subtypes of astrocytes operational in healthyand pathological nervous tissue.ACKNOWLEDGEMENTSThis work was supported by grants of the National Key R&D Programme of China(2019YFC1709101) and the Project First-Class Disciplines Development of ChengduUniversity of Traditional Chinese Medicine (CZYHW1901) awarded in order to buildup the “International Collaborative Centre on Big Science Plan for PurinergicSignalling”, and the Science and Technology Programme of Sichuan Province, China(2019YFH0108). The stay and work of PI in Chengdu was supported by a grant fromthe State Administration of Foreign Experts Affairs (G20190236012). A.S. and Y.T. aresupported by RFBR grant 21-54-53018 for the NSFC-RFBR project.REFERENCES1. Sanmarco, L. M. et al. Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes. Nature 590, 473–479 (2021).2. Penfield, W. In Special cytology, the form and function of the cell in health anddisease. (ed E. V. Cowdry) 1033–1068 (Hoeber, 1928).3. Escartin, C. et al. Reactive astrocyte nomenclature, definitions, and future direc-tions. Nat. Neurosci. 24, 312–325 (2021).4. Verkhratsky, A., Zorec, R. & Parpura, V. Stratification of astrocytes in healthy anddiseased brain. Brain Pathol. 27, 629–644 (2017).5. Sofroniew, M. V. Astrocyte reactivity: subtypes, states, and functions in CNS innateimmunity. Trends Immunol. 41, 758–770 (2020).Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in anymedium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directlyfrom the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2021Fig. 1 Anti-inflammatory astrocytes. The subpopulation of anti-inflammatory astrocytes is present in the spinal cord of mice andpossibly of humans.5 These astrocytes specifically express the lysosomalassociated protein 1 (LAMP1) and the death receptor ligand TRAIL; thelatter after being released activate death receptors on T lymphocytesinstigating their apoptosis. Expression of TRAIL in astrocytes iscontrolled by IFN-γ secreted by meningeal natural killer cells; IFN-γreaches astrocytic endfeet through subarachnoid cerebrospinal fluid.The IFN-γ natural killer cells are, in their turn, under control fromsystemic factors including the gut microbiome; depletion of the lattersubstantially reduces the number of IFN-γ secreting natural killer cellsThe anti-inflammatory astrocyte revealed: the role of the microbiome in. . .Verkhratsky et al.2Signal Transduction and Targeted Therapy           (2021) 6:150 

The Anti-Inflammatory Astrocyte Revealed: the Role of the Microbiome in Shaping Brain Defences

https://addi.ehu.es/bitstream/10810/51482/1/s41392-021-00577-5.pdf

The Anti-Inflammatory Astrocyte Revealed: the Role of the Microbiome in Shaping Brain Defences

Abstract

Similar works

Full text

Available Versions

The University of Manchester - Institutional Repository

The University of Manchester - Institutional Repository

Archivo Digital para la Docencia y la Investigación