Different types of reactive astrocyte are generated after various injuries and insults to the brain, but less is known about what these astrocyte subtypes do. Here, Shane Liddelow et al. describe how these reactive astrocytes are induced by neuroinflammatory microglia. The authors also explore the functional roles of reactive astrocytes in the progression of disease or damaged states, and show that A1 astrocytes contribute to the death of neurons in the central nervous system under certain conditions.
Glial Cells in Health and Disease
Glial cells – traditionally thought as simply the “glue” of the nervous system – are increasingly recognized to play a critical role in the development and function of the brain. Importantly, glial cell dysfunction has recently been shown to contribute to various neurological disorders, such as autism, schizophrenia, pain, and neurodegeneration. Understanding the function of glial cells under normal, physiological conditions, as well as how it goes awry in disease, has the potential to revolutionize how we think about the function and dysfunction of the nervous system, and inspire the development of new therapies to treat these devastating disorders.
In this Collection, we highlight the best research articles, reviews, and commentaries in the area of glial biology, published in the Nature Research journals, including Nature, Nature Communications, Nature Medicine, Nature Neuroscience, Nature Immunology, Nature Methods, Nature Reviews Immunology, Nature Reviews Neuroscience, and Nature Reviews Neurology, during 2016 and 2017. Findings in these papers will not only be valuable to the basic science community, but would also lay the groundwork for future translational research that aims to restore glial function and treat disorders of the nervous system.
Microglia are the macrophages of the CNS, with innate neuroimmune function, and play important roles in tissue homeostasis, CNS development and neurodegeneration. Here human microglial gene expression profiles were generated. Human and mouse microglia were highly similar, except for aging-regulated genes, indicating that microglial aging differs between humans and mice.
Microglia are CNS-resident macrophages, but studying their functions in health and disease has been challenging due to a lack of specific markers. Greter and colleagues identify the transcription factor Sall1 as being uniquely associated with microglia in the CNS, where it is important for defining their fate and homeostatic function.
Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia
μ opioid receptors (MORs) expressed on primary afferent nociceptor neurons are responsible for two maladaptive side-effects of chronic opioid use: opioid tolerance and opioid-induced hyperalgesia (pain). A combination therapy of opioid receptor agonism plus peripheral-restricted MOR antagonism abrogates these side-effects while preserving opioid analgesia in rodent models of peri-operative and chronic pain.
The contribution of glia to Huntington's disease is unclear. The authors show that human glial progenitor cells (GPCs) expressing mutant huntingtin impair motor performance when engrafted into wild type mice, and wild type human GPCs ameliorate disease phenotypes when engrafted into an HD mouse model.
Calcium signalling in glial cells has been proposed to participate in neuronal function but evidence has remained indirect and scattered. Now Marc Freeman and colleagues report that the octopamine/tyramine receptor (Oct-Tyr-R) and the transient receptor potential (TRP) channel Water witch (Wtrw) in Drosophila astrocytes are essential to neuromodulation between two classes of neurons, and to sensory-driven larval behaviour. This is the first in vivo demonstration of astrocyte calcium signalling as an obligatory intermediate in neuronal circuitry and animal behaviour.
Emerging results suggest that neurons can transfer damaged mitochondria into adjacent astrocytes for disposal and recycling. Here Eng Lo and colleagues identify a transfer of healthy mitochondria in the opposite direction. In a mouse model of ischaemia, the authors demonstrate the release of mitochondrial particles from astrocytes that are taken up by adjacent neurons, leading to enhanced cell survival signalling. Disrupting this transfer led to worsened neurological outcomes. These findings suggest a previously unknown form of crosstalk between glia and damaged neurons, and suggest pathways that may be potentially targeted for improving stroke recovery in the future.
Henrique Veiga-Fernandes and colleagues show that neurotrophic factors produced by enteric glial cells in response to microbiota-derived cues contribute to the interleukin-22 production and regulation of group 3 innate lymphoid cells in the gut. Disruption of this pathway leads to impaired clearance of Citrobacter rodentium and defects in epithelial integrity in a model of intestinal inflammation.
The development of novel therapeutic approaches to brain metastases has been hampered by a lack of mechanistic insights. These authors report that invasive breast and lung cancer cells engage the normally protective network of brain astrocytes to support metastases. By establishing gap junctions, tumour cells trigger the activation of innate immune response signalling in astrocytes, which then secrete factors that support metastatic growth and chemoresistance. The gap junction inhibitors meclofenamate and tonabersat interfere with this paracrine loop and impair the growth of experimental brain metastases, suggesting possible clinical relevance.
Disrupted gamma rhythms—oscillations in the brain's neuronal circuits at around 20–50 Hz—are hallmarks of various neurological disorders and have been seen in patients with Alzheimer's disease and specific mouse models of the disease. Li-Huei Tsai and colleagues show that gamma oscillations are also disrupted in the 5XFAD mouse model of Alzheimer's disease, and find reduced gamma prior to plaque formation and cognitive decline. Remarkably, by training neurons to oscillate at gamma frequency (40 Hz) in multiple mouse models including APP/PS1 and wild-type mice, amyloid-β peptide levels could be reduced.
Itay Tirosh et al. use single-cell RNA-seq to show that human oligodendrogliomas contain cancer cells specialized into two types of glia, as well as a rare subpopulation of cells that are undifferentiated and display a gene expression program that is characteristic of neural stem cells. By coupling this analysis with functional assessment of oligodendroglioma cell lines, the authors provide support for a cancer stem cell model of tumour development in this particular context.
A majority of West Nile virus (WNV) sufferers experience cognitive signs and symptoms, including memory dysfunction, but the mechanisms driving these impairments are largely unknown. Robyn Klein and colleagues demonstrate an enhancement of complement-mediated synaptic pruning in the hippocampus following WNV infection. This pruning required microglia and resembled developmental pruning by the same mechanism. Disruption of complement or microglia during infection protected animals from the WNV-induced memory deficits.
Microglial phagocytosis is required for neurogenic niche maintenance and response to central nervous system (CNS) injury. Here Greg Lemke and colleagues show that the TAM receptor kinases Mer and Axl are expressed by microglia and in the adult CNS, and mediate the clearance of apoptotic cells from the neurogenic niche. This work demonstrates that TAM receptors act as controllers of microglial physiology, and are potential targets for therapeutic intervention in CNS disease.
It is widely believed that the astrocytic scars that develop following central nervous system (CNS) injury are a major obstacle to subsequent axonal regrowth. But here Michael Sofroniew and colleagues demonstrate that limiting the formation of the scar actually attenuates axon re-growth. Sustained delivery of axon-specific growth factors not typically present in spinal cord lesions allowed for robust re-growth, but only if the astrocytic scar was present. These results question the prevailing dogma and suggest that astrocyte scarring promotes — rather than prevents — CNS axon regeneration post-injury.
The acquisition of a new skill or motor program is thought to be mediated by changes in neuronal plasticity at early stages of learning, which is later stabilized by new myelin generated by oligodendrocytes. In this study, the authors show that oligodendrocyte precursors exist in a ‘primed’ state, which allows them to contribute to early stages of motor learning.
The nature of astrocyte diversity in the adult brain has remained poorly defined. The authors identify five astrocyte subpopulations in the brain that exhibit extensive molecular and functional diversity. They uncover correlative populations in malignant glioma, providing insight into how diverse astrocyte populations contribute to synaptogenesis, tumor pathophysiology and neurological disease.
Neocortical resident microglia are long-lived cells. Füger et al. report that approximately half of these cells survive for the entire lifespan of a mouse. While microglial proliferation under homeostatic conditions is low, proliferation is increased in a mouse model of Alzheimer's disease.
Microglia are the tissue-resident macrophages of the brain. Ouyang and colleagues show the ER-resident transmembrane protein NRROS is necessary for proper development and function of microglia. Mice lacking NRROS exhibit neurologic defects and die prematurely.
Gliomas recruit and manipulate microglial function to promote their growth. Joseph and colleagues reveal the molecular basis of this manipulation by showing that gliomas trigger S-nitrosylation of microglial caspase-3 and thereby initiate a tumor-promoting phenotype.
Microglia progenitors seed the central nervous system from the yolk sac, but little is known about the origin of non-parenchymal macrophages. Prinz and colleagues demonstrate that these macrophages in the central nervous system are related to but distinct from microglia and are largely of embryonic origin.
The release of ATP from spinal microglia via pannexin-1 channels is required for withdrawal symptoms after termination of chronic opioid treatment in rodents, and pharmacological blockade of pannexin-1 channels reduces the severity of withdrawal without affecting opiate analgesia.
Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis
Expression of MHC class I molecules on motor neurons protects them from astrocyte-induced toxicity in ALS.
Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor
After upregulation of AHR in astrocytes by type I interferons, commensal-microbe-derived metabolites of dietary tryptophan act on astrocytes to suppress CNS inflammation.
In response to signals from afferent TRPV1+ C-fibers, STAT3-dependent upregulation of LCN2 in reactive astrocytes of the spinal dorsal horn amplifies itch signaling in multiple rodent models of atopic and contact dermatitis.
Interaction of reactive astrocytes with type I collagen induces astrocytic scar formation through the integrin–N-cadherin pathway after spinal cord injury
In a mouse model of spinal cord injury, reactive astrogliosis is found to be context dependent and reversible. Blockade of type I collagen–reactive astrocyte interactions prevents astrocyte scar formation and facilitates functional recovery after injury.
Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke
How microglia contribute to brain injury or repair is unclear. Here combining microglia manipulations and calcium imaging, the authors show that selective elimination of microglia leads to disrupted neuronal calcium dynamics and markedly increased brain injury after cerebral ischemia.
Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling
Core clock genes, such asBmal1, are expressed in astrocytes, but their contribution to the timekeeping system is unknown. Barca-Mayo et al. report that deletion of Bmal1in Glast+ astrocytes alters the neuronal clock through GABA signalling, leading to abnormal circadian locomotor behaviour and impaired cognition in mice.
Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain
While transcranical direct current stimulation (tDCS) is used in clinical setting, its cellular mechanism of action is unclear. Here, Hajime Hirase and colleagues visualize cellular response in mouse brain to tDCS and show robust astrocyte activation that coincide with plasticity changes.
Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury
Microglia and monocytes contribute to neuropathic pain states, but the precise role of the two cell types is not clear. Here Peng et al.use temporally controlled ablation of monocytes and microglia in mice to show that these cells work together to initiate neuropathic-pain like behaviour, but are less important in the maintenance phase.
Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism
How neurons and neuronal activity regulate astrocyte functions is poorly understood. Haselet al. identify two large groups of astrocytic genes that are regulated by neuronal contact and synaptic activity respectively, with distinct roles in astrocytic function; interestingly, many of these genes are dysregulated in neurodegeneration.
Glial scars are thought to provide a biochemical and mechanical barrier to neuronal regeneration post-injury, but the mechanical properties of the scars have not been studied in detail. Here the authors perform atomic force microscopy measurements of glial scars from the injured rat cortex and spinal cord, and find that brain tissue softens in response to the injury.
Hidden hearing loss (HHL) is an auditory neuropathy that impairs one’s ability to hear, particularly in a noisy environment. Here the authors show that in mice, transient loss of cochlear Schwann cells results in permanent disruption of the cochlear heminodal structure, leading to auditory deficits characteristic of HHL.
Reviews and Perspectives
Microglia are by far the best-characterized macrophages in the CNS, but non-parenchymal populations, such as those found in the meninges, are being increasingly studied. Prinz et al. review the ontogeny and functions of both parenchymal macrophages and non-parenchymal macrophages the CNS.
Emerging evidence suggests that astrocytes may be as diverse in their physiological and functional characteristics as neurons. Ben Haim and Rowitch describe astrocyte heterogeneity, consider the mechanisms by which such diversity may arise and discuss the consequences of its disruption in disease.
Central and peripheral inflammation can be induced by psychological stress and is associated with depressive symptoms, suggesting a possible role for immune dysfunction in depression. Duman and colleagues examine the neuroimmune mechanisms influencing neuronal–microglial interactions, neuronal activity and synaptic plasticity in stress and depression.
Dynamic membrane transformations are not exclusively controlled by cytoskeletal rearrangement, but also by biophysical constraints, adhesive forces, membrane curvature and compaction. Recent technological advances have helped clarify longstanding controversies concerning myelination, from target selection to axon wrapping and membrane compaction. Chang et al. review these findings and discuss how understanding these processes provides insight into myelination-centered mechanisms of neural plasticity.
Effective drug treatments for intracerebral haemorrhage (ICH) are still lacking. However, therapies that target microglial phenotype switching might soon become available for affected patients. Here, Wang and colleagues summarize key advances in understanding of microglial function after ICH, including modulators of microglial function and interactions with other cells.
In this Review, Salter and Stevens discuss the role of microglia in CNS disorders such as autism, neurodegenerative disorders, Alzheimer’s disease, and chronic pain.
During late-stage development, supernumerary synapses are eliminated in a process known as synaptic pruning. Here, Neniskyte and Gross give an overview of synaptic pruning in various parts of the nervous system and describe how differences in synaptic pruning may be associated with neurodevelopmental disorders.
The role of transient elevations of the intracellular concentration of calcium in astrocytes is controversial. Some neuroscientists believe that, by triggering the release of 'gliotransmitters', astrocyte calcium transients regulate synaptic strength and neuronal excitability, while others deny that gliotransmission exists. Bazargani and Attwell assess the status of this rapidly evolving field.
Tumor-associated macrophages (TAMs) establish a permissive microenvironment that positively influences glioma formation, progression and response to treatment. TAMs elaborate growth factors and cytokines that collectively facilitate tumor proliferation, survival and migration. Defining the distinct roles of these stromal cells in the glioma ecosystem may yield new opportunities for therapeutic targeting.
Reactive astrocytes have been proposed to become incompetent bystanders in epilepsy as a result of cellular changes rendering them incapable of performing housekeeping tasks. This review discusses new research that suggests that reactive astrocytes may drive the disease process by impairing the inhibitory action of neuronal GABA receptors.
In the twenty-first century, microglia came of age. Their remarkable ontogeny, unique functions and gene expression profile, process motility, and disease relevance have all been highlighted. Neuroscientists interested in microglia encounter an obsolete concept, M1/M2 polarization, suggesting experimental strategies that produce neither conceptual nor technical advances. Ransohoff's Perspective argues against applying this flawed paradigm.
This Review describes the distinct mononuclear phagocyte system (MPS) cells that are found in the different compartments of the eye. The authors discuss the importance of MPS cells for maintaining tissue homeostasis and explain how these cells contribute to eye pathology following a loss of immune privilege.
Cerebral blood flow regulation is essential for normal brain function. In this Review, Kisler and colleagues examine the cellular and molecular mechanisms that underlie cerebral blood flow regulation at the arteriole and capillary level, and how neurovascular dysfunction contributes to neurodegenerative disorders such as Alzheimer disease.
Neuroinflammation can cause acute secondary injury after traumatic brain injury (TBI), and has been linked to chronic neurodegenerative diseases; however, anti-inflammatory agents have failed to improve TBI outcomes in clinical trials. In this Review, the authors propose a new framework for targeted immunomodulation after TBI.
A series of genetic studies has implicated the microglial immune receptor TREM2 in the pathogenesis of Alzheimer disease (AD). Here, Colonna and Wang describe recent studies that have begun to unpick the mechanisms by which TREM2 is involved in AD and discuss unanswered questions in the field.
Recent studies suggest that progranulin has an important role in lysosome biogenesis and innate immunity in the brain. In this Progress article, Kao and colleagues suggest that progranulin also plays a part in suppressing excessive neuroinflammation during ageing.
The precise timing of impulse transmission along axons is crucial for synaptic plasticity and brain oscillations, and is partly determined by myelin thickness. In this Opinion article, R. Douglas Fields discusses how electrical activity influences myelin thickness and thus conduction velocity and circuit properties.
Researchers have developed a protocol for differentiation of microglia-like cells from human pluripotent stem cells.
A new study shows that astrocytic scars facilitate the regrowth of axons following spinal cord injury in mice.
Components of the complement cascade induce microglial engulfment of synapses to mediate synapse loss in mouse models of Alzheimer disease.
In experimental autoimmune encephalitis (a mouse model of multiple sclerosis), type I interferons stimulate the production of aryl hydrocarbon receptor, which is activated by diet- and microbe-derived molecules and limits CNS inflammation.
Activated microglia induce a subtype of reactive astrocytes that is toxic to various neuronal types and oligodendrocytes and that is found in various neurological disorders.
A new study describes a method for differentiating human and murine induced pluripotent stem cells into microglia-like cells.
A multicolor reporter mouse model enables monitoring of the fate and dynamics of microglia in health and disease.
Wakefulness influences synaptic function in the hippocampus through the modulation of NMDA receptor co-agonist availability by astrocytes.
Disease progression in a mouse model of Alzheimer disease is associated with the appearance of a population of disease-associated microglia that can phagocytose amyloid-β.
Methods and Protocols
Microglia can expand and divide quickly in the context of CNS pathology, but little is known about the kinetics and clonality of microgliosis. Prinz and colleagues develop a new fate mapping system to monitor microglial dynamics. Microglial self-renewal is found to be a stochastic process under steady state conditions, whereas clonal expansion is observed during disease.
Adaptive optics can counteract optical aberrations within tissues, but the field of view is typically limited. Multi-pupil adaptive optics expands the area that can be imaged, and this is demonstrated by multiple applications in the mouse brain imaging.
A protocol is developed to enable the differentiation of microglial-like cells from human pluripotent stem cells, which are shown to resemble primary human microglia, integrate into 3D neuronal cultures, and perform phagocytic and injury-response functions.
Pandya et al. describe a protocol to differentiate human and mouse iPSCs into cells with the phenotype, transcriptional profile and functional properties of microglia. The treatment of murine intracranial malignant gliomas with these cells demonstrates their potential clinical use. These microglia-like cells will enable further studies into the role of microglia in health and disease.
A method for 3D differentiation of human pluripotent stem cells yields brain cortical spheroids with functional neurons and astrocytes. The spheroids can be sliced for imaging and electrophysiological studies.
The Fixed and Recovered Intact Single-cell RNA (FRISCR) method enables robust RNA extraction and sequencing from fixed, stained and sorted single cells and allows unprecedented profiling of rare cell types, including two subpopulations of radial glial cells in the developing human cortex.