Review
Astrocytes and Microglia: In Sickness and in Health

https://doi.org/10.1016/j.tins.2020.01.003Get rights and content

Highlights

  • Astrocytes and microglia perform complementary roles during brain development and physiology. Among the best studied of these are their roles in supporting synapse development and responding to neuronal signals. Astrocytes and microglia may coordinate their supportive functions in other, less studied physiologic processes, including myelination, blood–brain barrier regulation, and angiogenesis.

  • In response to injury, inflammation, and degenerative diseases, context-specific signals can shape both astrocyte and microglial responses. This type of synchrony in the astrocytic–microglial unit has been demonstrated in mouse models of Alzheimer’s disease, multiple sclerosis, and encephalitis.

  • Molecular mechanisms that regulate astrocyte–microglia communication include direct signaling through cytokines and other molecules, as well as distinct but coordinated responses to shared environmental signals such as purines and norepinephrine. In pathology, blood-derived factors help to synchronize the astrocyte–microglia unit.

Healthy central nervous system (CNS) development and function require an intricate and balanced bidirectional communication between neurons and glia cells. In this review, we discuss the complementary roles of astrocytes and microglia in building the brain, including in the formation and refinement of synapses. We discuss recent evidence demonstrating how these interactions are coordinated in the transition from healthy physiology towards disease and discuss known and potential molecular mechanisms that mediate this cellular crosstalk.

Section snippets

The Bond between Astrocytes and Microglia

Like many great duos, astrocytes and microglia in the central nervous system (CNS) have a unique bond that constrains and coordinates their functions. The brain is functionally dominated by its most specialized cell type, neurons, electrically active cells evolved for intercellular communication. Yet, as in other organs, brain function depends on a village of cell types whose functions are relatively conserved across multiple tissues, including vascular endothelial cells, pericytes, and

Astrocytes and Microglia Promote Developmental Synapse Formation and Pruning

Both astrocytes and microglia play critical roles in neural circuit formation during development, particularly in support of synapse formation and remodeling. Astrocytes surround and contact most neuronal synapses, as well as forming the borders of the brain and vasculature. Studies over the past two decades have identified multiple molecules released from astrocytes that promote neuronal synapse formation. These include glypicans 4 and 6, thrombospondin 1 and 2, and hevin (Sparcl1) (reviewed

Molecular Mechanisms of Astrocyte Microglial Communication in Pathology

Recent work has begun to reveal several molecular mechanisms by which astrocyte and microglial function is synchronized and, more often than not, these mechanisms are studied in the context of pathology. In the sections below, we will review some of the signaling molecules that coordinate the function of astrocytes and microglia across a range of perturbations (Figure 3). We focus on selected examples where recent literature indicates direct interactions between astrocytes and microglia, or

Concluding Remarks

Recent advances in single-cell analysis have changed the landscape of science and have the potential to reveal synchronized responses among multiple cell types in the brain. Single-cell data has already opened up new approaches to understanding microglia and revealed novel microglial and myeloid subsets in inflammatory conditions, including a disease associated microglial signature that may be conserved in several different pathologies [63., 64., 65.,110]. This subset represented 7% of cells in

Acknowledgments

Thanks to Ari Molofsky and members of the Anna Molofsky lab for helpful discussion and comments on the manuscript and to funding from NIMH (R01 MH119349), the Pew Charitable Trusts, and the Burroughs Wellcome Fund.

References (111)

  • Y. Li

    Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo

    Dev. Cell

    (2012)
  • A. Panatier et al.

    The soothing touch: microglial contact influences neuronal excitability

    Dev. Cell

    (2012)
  • R.A. España

    Norepinephrine at the nexus of arousal, motivation and relapse

    Brain Res.

    (2016)
  • M. Paukert

    Norepinephrine controls astroglial responsiveness to local circuit activity

    Neuron

    (2014)
  • D. Gosselin

    Environment drives selection and function of enhancers controlling tissue-specific macrophage identities

    Cell

    (2014)
  • Y. Lavin

    Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment

    Cell

    (2014)
  • A.B. Molofsky

    Interleukin-33 in tissue homeostasis, injury, and inflammation

    Immunity

    (2015)
  • S.P. Gadani

    The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury

    Neuron

    (2015)
  • Y. Pomeshchik

    Interleukin-33 treatment reduces secondary injury and improves functional recovery after contusion spinal cord injury

    Brain Behav. Immun.

    (2015)
  • Q. Luo

    Interleukin-33 protects ischemic brain injury by regulating specific microglial activities

    Neuroscience

    (2018)
  • R. Chovatiya et al.

    Stress, inflammation, and defense of homeostasis

    Mol. Cell

    (2014)
  • V.N. Mutafova-Yambolieva et al.

    The purinergic neurotransmitter revisited: a single substance or multiple players?

    Pharmacol. Ther.

    (2014)
  • U.B. Eyo

    P2Y12R-dependent translocation mechanisms gate the changing microglial landscape

    Cell Rep.

    (2018)
  • Y. Shinozaki

    Transformation of astrocytes to a neuroprotective phenotype by microglia via P2Y1 receptor downregulation

    Cell Rep.

    (2017)
  • F. Ginhoux et al.

    Origin of microglia: current concepts and past controversies

    Cold Spring Harb. Perspect. Biol.

    (2015)
  • A.V. Molofsky et al.

    Astrocyte development: a guide for the perplexed

    Glia

    (2015)
  • D. Davalos

    ATP mediates rapid microglial response to local brain injury in vivo

    Nat. Neurosci.

    (2005)
  • A. Nimmerjahn

    Neuroscience: resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo

    Science

    (2005)
  • C. Madry

    Microglial ramification, surveillance, and interleukin-1b release are regulated by the two-pore domain K+ channel THIK-1

    Neuron

    (2018)
  • J. Bruttger

    Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system

    Immunity

    (2015)
  • A.R. Najafi

    A limited capacity for microglial repopulation in the adult brain

    Glia

    (2018)
  • Y. Huang

    Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion

    Nat. Neurosci.

    (2018)
  • J. Silver et al.

    Regeneration beyond the glial scar

    Nat. Rev. Neurosci.

    (2004)
  • M.V. Sofroniew

    Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators

    Neuroscientist

    (2014)
  • L.E. Clarke et al.

    Emerging roles of astrocytes in neural circuit development

    Nat. Rev. Neurosci.

    (2013)
  • R.C. Paolicelli

    Synaptic pruning by microglia is necessary for normal brain development

    Science

    (2011)
  • F. Filipello

    The microglial innate immune receptor TREM2 is required for synapse elimination and normal brain connectivity

    Immunity

    (2018)
  • W. Chung

    Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways

    Nature

    (2013)
  • Y. Fuentes-Medel

    Glia and muscle sculpt neuromuscular arbors by engulfing destabilized synaptic boutons and shed presynaptic debris

    PLoS Biol.

    (2009)
  • O.E. Tasdemir-Yilmaz et al.

    Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons

    Genes Dev.

    (2014)
  • A.R. Bialas et al.

    TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement

    Nat. Neurosci.

    (2013)
  • I.D. Vainchtein

    Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development

    Science

    (2018)
  • C.Z. Han

    Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation

    Nature

    (2016)
  • M. Ueno

    Layer V cortical neurons require microglial support for survival during postnatal development

    Nat. Neurosci.

    (2013)
  • J. Tønnesen

    Super-resolution imaging of the extracellular space in living brain tissue

    Cell

    (2018)
  • C. Bonnans

    Remodelling the extracellular matrix in development and disease

    Nat. Rev. Mol. Cell Biol.

    (2014)
  • Y. Zhang

    An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex

    J. Neurosci.

    (2014)
  • K.W. Kelley

    Variation among intact tissue samples reveals the core transcriptional features of human CNS cell classes

    Nat. Neurosci.

    (2018)
  • R.Y. Tsien

    Very long-term memories may be stored in the pattern of holes in the perineuronal net

    Proc. Natl. Acad. Sci. U. S. A.

    (2013)
  • M. Segel

    Niche stiffness underlies the ageing of central nervous system progenitor cells

    Nature

    (2019)
  • Cited by (267)

    View all citing articles on Scopus
    View full text