Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological ...appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.
Astrocyte roles in traumatic brain injury Burda, Joshua E.; Bernstein, Alexander M.; Sofroniew, Michael V.
Experimental neurology,
01/2016, Volume:
275, Issue:
3
Journal Article
Peer reviewed
Open access
Astrocytes sense changes in neural activity and extracellular space composition. In response, they exert homeostatic mechanisms critical for maintaining neural circuit function, such as buffering ...neurotransmitters, modulating extracellular osmolarity and calibrating neurovascular coupling. In addition to upholding normal brain activities, astrocytes respond to diverse forms of brain injury with heterogeneous and progressive changes of gene expression, morphology, proliferative capacity and function that are collectively referred to as reactive astrogliosis. Traumatic brain injury (TBI) sets in motion complex events in which noxious mechanical forces cause tissue damage and disrupt central nervous system (CNS) homeostasis, which in turn trigger diverse multi-cellular responses that evolve over time and can lead either to neural repair or secondary cellular injury. In response to TBI, astrocytes in different cellular microenvironments tune their reactivity to varying degrees of axonal injury, vascular disruption, ischemia and inflammation. Here we review different forms of TBI-induced astrocyte reactivity and the functional consequences of these responses for TBI pathobiology. Evidence regarding astrocyte contribution to post-traumatic tissue repair and synaptic remodeling is examined, and the potential for targeting specific aspects of astrogliosis to ameliorate TBI sequelae is considered.
•Astrocytes respond to diverse forms of TBI with changes of gene expression, morphology, proliferation and function.•Astrocytes tune their reactivity to varying degrees of axonal and vascular injury, ischemia and inflammation after TBI.•Astrocytes regulate brain inflammation and blood-brain barrier permeability after TBI.•Astrocytes significantly contribute to post-traumatic tissue repair and synaptic remodeling following TBI.
Astrocytes are neural parenchymal cells that ubiquitously tile the central nervous system (CNS). In addition to playing essential roles in healthy tissue, astrocytes exhibit an evolutionarily ancient ...response to all CNS insults, referred to as astrocyte reactivity. Long regarded as passive and homogeneous, astrocyte reactivity is being revealed as a heterogeneous and functionally powerful component of mammalian CNS innate immunity. Nevertheless, concepts about what astrocyte reactivity comprises and what it does are incomplete and sometimes controversial. This review discusses the goal of differentiating reactive astrocyte subtypes and states based on composite pictures of molecular expression, cell morphology, cellular interactions, proliferative state, normal functions, and disease-induced dysfunctions. A working model and conceptual framework is presented for characterizing the diversity of astrocyte reactivity.
Astrocyte reactivity in response to different central nervous system (CNS) disorders is diverse and context-dependent, and can be functionally powerful.Reactive astrocytes exhibit at least two broad overarching subtypes: (i) proliferative border-forming reactive astrocytes that surround areas of overt tissue damage, and (ii) nonproliferative reactive astrocytes that retain their basic structure and cellular interactions in essentially intact but reactive neural tissue.Normal astrocyte reactivity is an evolutionarily ancient response that can protect neural tissue, maintain tissue homeostasis, and preserve neurological functions after diverse CNS insults.Dysfunction of reactive astrocytes can contribute to CNS disorders either through loss of normal functions or through gain of abnormal functions.Reactive astrocytes express damage-associated molecular patterns (DAMP) and pathogen-associated molecular pattern (PAMP) receptors, and are emerging as integral and essential components of multicellular CNS innate immunity.
Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses
. By contrast, astrocytes are under neuronal control ...through specific neurotransmitter receptors
. However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses is unclear. Here we show that activation of mouse astroglial type-1 cannabinoid receptors associated with mitochondrial membranes (mtCB
) hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioural responses in social interaction assays. Specifically, activation of astroglial mtCB
receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4, which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the hypoxia-inducible factor 1 pathway, eventually resulting in neuronal redox stress and impairment of behavioural responses in social interaction assays. Genetic and pharmacological correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behaviour. These findings suggest that mtCB
receptor signalling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behaviour in mice.
Perisynaptic astrocytic processes are an integral part of central nervous system synapses
; however, the molecular mechanisms that govern astrocyte-synapse adhesions and how astrocyte contacts ...control synapse formation and function are largely unknown. Here we use an in vivo chemico-genetic approach that applies a cell-surface fragment complementation strategy, Split-TurboID, and identify a proteome that is enriched at astrocyte-neuron junctions in vivo, which includes neuronal cell adhesion molecule (NRCAM). We find that NRCAM is expressed in cortical astrocytes, localizes to perisynaptic contacts and is required to restrict neuropil infiltration by astrocytic processes. Furthermore, we show that astrocytic NRCAM interacts transcellularly with neuronal NRCAM coupled to gephyrin at inhibitory postsynapses. Depletion of astrocytic NRCAM reduces numbers of inhibitory synapses without altering glutamatergic synaptic density. Moreover, loss of astrocytic NRCAM markedly decreases inhibitory synaptic function, with minor effects on excitation. Thus, our results present a proteomic framework for how astrocytes interface with neurons and reveal how astrocytes control GABAergic synapse formation and function.
Central nervous system (CNS) maintains a high level of metabolism, which leads to the generation of large amounts of free radicals, and it is also one of the most vulnerable organs to oxidative ...stress. Emerging evidences have shown that, as the key homeostatic cells in CNS, astrocytes are deeply involved in multiple aspects of CNS function including oxidative stress regulation. Besides, the redox level in CNS can in turn affect astrocytes in morphology and function. The complex and multiple roles of astrocytes indicate that their correct performance is crucial for the normal functioning of the CNS, and its dysfunction may result in the occurrence and progression of various neurological disorders. To date, the influence of astrocytes in CNS oxidative stress is rarely reviewed. Therefore, in this review we sum up the roles of astrocytes in redox regulation and the corresponding mechanisms under both normal and different pathological conditions.
Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found ...that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1β production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1β receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1β production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.
•Astroglia menin deficiency leads to depressive-like behaviors in mice•Menin reduction in astrocytes promotes IL-1β generation through NF-κB activation•NF-κB and IL-1β inhibitors attenuate the depressive-like phenotypes•A MEN1 SNP associated with MDD risk leads to aberrant NF-κB activation
Mechanisms underlying astrocyte-mediated neuroinflammation in depression remain unclear. Menin regulates NF-κB activity in astrocytes to promote neuroinflammation. Clinically, a MEN1 SNP is associated with the onset of depression. This study reveals a distinct role for menin in neuroinflammation and depression.
To elucidate whether interleukin-18 (IL-18) or interferon-Isup3 (IFN-Isup3) participates in neurodegeneartion, we investigated the changes in IL-18 and IFN-Isup3 systems within the rat hippocampus ...following status epilepticus (SE). In non-SE induced animals, IL-18, IL-18 receptor a (IL-18Ra), IFN-Isup3 and IFN-Isup3 receptor a (IFN-Isup3Ra) immunoreactivity was not detected in the hippocampus. Following SE, IL-18 immunoreactivity was increased in CA1-3 pyramidal cells as well as dentate granule cells. IL-18 immunoreactivity was also up-regulated in astrocytes and microglia/macrophages. IL-18Ra immunoreactivity was detected in astrocytes and microglia/macrophages. IFN-Isup3 immunoreactivity was detected only in astrocytes within all regions of the hippocampus. IFN-Isup3Ra immunoreactivity was increased in neurons as well as astrocytes. Intracerebroventricular infusions of recombinant rat IL-18 or IFN-Isup3 alleviated SE-induced neuronal damages, while neutralization of IL-18, IFN-Isup3 or their receptors aggravated them, as compared to saline-infused animals. These findings suggest that astroglial-mediated IFN-Isup3 pathway in response to IL-18 induction may play an important role in alleviation of SE-induced neuronal damages.
Many lines of evidence suggest that the Parkinson's disease (PD)-related protein α-synuclein (α-SYN) can propagate from cell to cell in a prion-like manner. However, the cellular mechanisms behind ...the spreading remain elusive. Here, we show that human astrocytes derived from embryonic stem cells actively transfer aggregated α-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess α-SYN oligomers results in α-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances. The stressed astrocytes respond by conspicuously sending out TNTs, enabling intercellular transfer of α-SYN to healthy astrocytes, which in return deliver mitochondria, indicating a TNT-mediated rescue mechanism. Using a pharmacological approach to inhibit TNT formation, we abolished the transfer of both α-SYN and mitochondria. Together, our results highlight the role of astrocytes in α-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance.
Astrocytes are the major cell type in the brain, yet their role in Parkinson's disease progression remains elusive. Here, we show that human astrocytes actively transfer aggregated α-synuclein (α-SYN) to healthy astrocytes via direct contact and tunneling nanotubes (TNTs), rather than degrade it. The astrocytes engulf large amounts of oligomeric α-SYN that are subsequently stored in the trans-Golgi network region. The accumulation of α-SYN in the astrocytes affects their lysosomal machinery and induces mitochondrial damage. The stressed astrocytes respond by sending out TNTs, enabling intercellular transfer of α-SYN to healthy astrocytes. Our findings highlight an unexpected role of astrocytes in the propagation of α-SYN pathology via TNTs, revealing astrocytes as a potential target for therapeutic intervention.
Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, ...transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of the C2 domain in cytosolic phospholipase A2 (cPLA2) with the CARD domain in mitochondrial antiviral signaling protein (MAVS), boosting NF-κB-driven transcriptional programs that promote CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitment to MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymatic activity and the production of lactate involved in the metabolic support of neurons. Miglustat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlines a new role for MAVS in CNS inflammation, and identifies candidate targets for therapeutic intervention.
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•Sphingolipid drives astrocyte pathogenic activities via cPLA2-MAVS-NF-κB•cPLA2 displaces HK2 from MAVS, limiting the metabolic support of neurons by astrocytes•Miglustat suppresses astrocyte cPLA2-MAVS-NF-κB pro-inflammatory signaling•Miglustat is a candidate drug for repurposing to treat secondary progressive MS
By exploring the immunometabolic pathways that drive pro-inflammatory astrocyte activities, sphingolipid metabolism is identified as a promising therapeutic target in CNS inflammation.
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