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    Activated human astrocyte-derived extracellular vesicles modulate neuronal uptake, differentiation and firing. You Yang,Borgmann Kathleen,Edara Venkata Viswanadh,Stacy Satomi,Ghorpade Anuja,Ikezu Tsuneya Journal of extracellular vesicles Astrocytes in the central nervous system (CNS) provide supportive neural functions and mediate inflammatory responses from microglia. Increasing evidence supports their critical roles in regulating brain homoeostasis in response to pro-inflammatory factors such as cytokines and pathogen/damage-associated molecular pattern molecules in infectious and neurodegenerative diseases. However, the underlying mechanisms of the trans-cellular communication are still unclear. Extracellular vesicles (EVs) can transfer a large diversity of molecules such as lipids, nucleic acids and proteins for cellular communications. The purpose of this study is to characterize the EVs cargo proteins derived from human primary astrocytes (ADEVs) under both physiological and pathophysiological conditions. ADEVs were isolated from human primary astrocytes after vehicle (CTL) or interleukin-1β (IL-1β) pre-treatment. Label-free quantitative proteomic profiling revealed a notable up-regulation of proteins including actin-associated molecules, integrins and major histocompatibility complex in IL-1β-ADEVs compared to CTL-ADEVs, which were involved in cellular metabolism and organization, cellular communication and inflammatory response. When fluorescently labelled ADEVs were added into primary cultured mouse cortical neurons, we found a significantly increased neuronal uptake of IL-1β-ADEVs compared to CTL-ADEVs. We further confirmed it is likely due to the enrichment of surface proteins in IL-1β-ADEVs, as IL-1β-ADEVs uptake by neurons was partially suppressed by a specific integrin inhibitor. Additionally, treatment of neurons with IL-1β-ADEVs also reduced neurite outgrowth, branching and neuronal firing. These findings provide insight for the molecular mechanism of the ADEVs' effects on neural uptake, neural differentiation and maturation, and its alteration in inflammatory conditions. 10.1080/20013078.2019.1706801
    Astrocytes and neuroinflammation in Alzheimer's disease. Phillips Emma C,Croft Cara L,Kurbatskaya Ksenia,O'Neill Michael J,Hutton Michael L,Hanger Diane P,Garwood Claire J,Noble Wendy Biochemical Society transactions Increased production of amyloid β-peptide (Aβ) and altered processing of tau in Alzheimer's disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases. 10.1042/BST20140155
    APOE genotype-dependent modulation of astrocyte chemokine CCL3 production. Cudaback Eiron,Yang Yue,Montine Thomas J,Keene C Dirk Glia Apolipoprotein E (apoE) is well known as a regulator of cholesterol homeostasis, and is increasingly recognized to play a prominent role in the modulation of innate immune response, including cell-to-cell communication and migration. Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder characterized by neuroinflammation that appears to be an important component of the pathophysiology of the disease. Astrocytes are the majority cell type in brain, exerting significant influence over a range of central nervous system activities, including microglial-mediated neuroinflammatory responses. As the resident innate immune effector cells of the brain, microglia respond to soluble chemical signals released from tissue during injury and disease by mobilizing to lesion sites, clearing toxic molecules, and releasing chemical signals of their own. While microglial-mediated neuroinflammation in the AD brain remains an area of intense investigation, the mechanisms underlying reinforcement and regulation of these aberrant microglial responses by astrocytes are largely unstudied. Moreover, although inheritance of APOE ɛ4 represents the greatest genetic risk factor for sporadic AD, the mechanism by which apoE isoforms differentially influence AD pathophysiology is unknown. Here we show that APOE ɛ4 genotype specifically modulates astrocyte secretion of potent microglial chemotactic agents, including CCL3, thus providing evidence that APOE modulation of central nervous system (CNS) innate immune response is mediated through astrocytes. 10.1002/glia.22732
    Cell-to-cell Communication by Extracellular Vesicles: Focus on Microglia. Paolicelli Rosa C,Bergamini Giorgio,Rajendran Lawrence Neuroscience Extracellular vesicles, including exosomes and microvesicles, are small, nano-to-micrometer vesicles that are released from cells. While initially observed in immune cells and reticulocytes as vesicles meant to remove archaic proteins, now they have been observed in almost all cell types of multicellular organisms. Growing evidence indicates that extracellular vesicles, containing lipids, proteins and RNAs, represent an efficient way to transfer functional cargoes from one cell to another. In the central nervous system, the extensive cross-talk ongoing between neurons and glia, including microglia, the immune cells of the brain, takes advantage of secreted vesicles, which mediate intercellular communication over long range distance. Recent literature supports a critical role for extracellular vesicles in mediating complex and coordinated communication among neurons, astrocytes and microglia, both in the healthy and in the diseased brain. In this review, we focus on the biogenesis and function of microglia-related extracellular vesicles and focus on their putative role in Alzheimer's disease pathology. 10.1016/j.neuroscience.2018.04.003
    Pharmacological Tools to Study the Role of Astrocytes in Neural Network Functions. Peña-Ortega Fernando,Rivera-Angulo Ana Julia,Lorea-Hernández Jonathan Julio Advances in experimental medicine and biology Despite that astrocytes and microglia do not communicate by electrical impulses, they can efficiently communicate among them, with each other and with neurons, to participate in complex neural functions requiring broad cell-communication and long-lasting regulation of brain function. Glial cells express many receptors in common with neurons; secrete gliotransmitters as well as neurotrophic and neuroinflammatory factors, which allow them to modulate synaptic transmission and neural excitability. All these properties allow glial cells to influence the activity of neuronal networks. Thus, the incorporation of glial cell function into the understanding of nervous system dynamics will provide a more accurate view of brain function. Our current knowledge of glial cell biology is providing us with experimental tools to explore their participation in neural network modulation. In this chapter, we review some of the classical, as well as some recent, pharmacological tools developed for the study of astrocyte's influence in neural function. We also provide some examples of the use of these pharmacological agents to understand the role of astrocytes in neural network function and dysfunction. 10.1007/978-3-319-40764-7_3
    Astrocyte-immune cell interactions in physiology and pathology. Han Rafael T,Kim Rachel D,Molofsky Anna V,Liddelow Shane A Immunity Astrocytes play both physiological and pathological roles in maintaining central nervous system (CNS) function. Here, we review the varied functions of astrocytes and how these might change in subsets of reactive astrocytes. We review the current understanding of astrocyte interactions with microglia and the vasculature and protective barriers in the central nervous system as well as highlight recent insights into physiologic and reactive astrocyte sub-states identified by transcriptional profiling. Our goal is to stimulate inquiry into how these molecular identifiers link to specific functional changes in astrocytes and to define the implications of these heterogeneous molecular and functional changes in brain function and pathology. Defining these complex interactions has the potential to yield new therapies in CNS injury, infection, and disease. 10.1016/j.immuni.2021.01.013
    TGFβ produced by IL-10 redirected astrocytes attenuates microglial activation. Norden Diana M,Fenn Ashley M,Dugan Allison,Godbout Jonathan P Glia While there clearly is an intimate relationship between astrocytes and microglia, few studies have examined these potentially dynamic interactions. In this study, cytokine-mediated communication between microglia and astrocytes under inflammatory conditions was investigated. We have previously shown that activated microglia produce Interleukin (IL)-10, a regulatory cytokine that plays an important role in resolving neuroinflammation. Nonetheless, the mechanism by which IL-10 attenuates pro-inflammatory cytokine expression in the brain is unclear. Here, we show that IL-10 redirected astrocytes regulate the activation of microglia in a transforming growth factor (TGF)-β dependent manner. In support of this concept, astrocytes in the brain maintained higher IL-10 receptor (IL-10R1) expression and primary astrocytes in culture were markedly more sensitive to the anti-inflammatory effects of IL-10 compared with microglia. Moreover, studies using primary cultures and an astrocyte-microglia coculture system revealed that astrocytes mediated the anti-inflammatory effects of IL-10 on microglia through the production of TGFβ. For instance, only when astrocytes were present did IL-10 stimulation reduce the expression of IL-1β and increase expression of anti-inflammatory mediators fractalkine receptor (CX3 CR1) and interleukin 4 receptor-α (IL-4Rα) in microglia. Importantly, these IL-10-astrocyte dependent effects on microglia were blocked by a TGFβ inhibitor. Furthermore, inhibition of TGFβ signaling in the brain resulted in prolonged sickness behavior and amplified pro-inflammatory cytokine expression in mice challenged with lipopolysaccharide. Taken together, IL-10 stimulated the production of TGFβ by astrocytes, which in turn, attenuated microglial activation. Overall, these findings provide novel insight into the mechanisms by which astrocytes modulate microglia under inflammatory conditions. 10.1002/glia.22647
    Astrocyte galectin-9 potentiates microglial TNF secretion. Steelman Andrew J,Li Jianrong Journal of neuroinflammation BACKGROUND:Aberrant neuroinflammation is suspected to contribute to the pathogenesis of myriad neurological diseases. As such, determining the pathways that promote or inhibit glial activation is of interest. Activation of the surface glycoprotein T-cell immunoglobulin and mucin-domain containing protein 3 (Tim-3) by the lectin galectin-9 has been implicated in promoting innate immune cell activation by potentiating or synergizing toll-like receptor (TLR) signaling. In the present study we examined the role of the Tim-3/galectin-9 pathway in glial activation in vitro. METHOD:Primary monocultures of microglia or astrocytes, co-cultures containing microglia and astrocytes, and mixed glial cultures consisting of microglia, astrocytes and oligodendrocytes were stimulated with poly(I:C) or LPS, and galectin-9 up-regulation was determined. The effect of endogenous galectin-9 production on microglial activation was examined using cultures from wild-type and Lgals9 null mice. The ability for recombinant galectin-9 to promote microglia activation was also assessed. Tim-3 expression on microglia and BV2 cells was examined by qPCR and flow cytometry and its necessity in transducing the galectin-9 signal was determined using a Tim-3 specific neutralizing antibody or recombinant soluble Tim-3. RESULT:Astrocytes potentiated TNF production from microglia following TLR stimulation. Poly(I:C) stimulation increased galectin-9 expression in microglia and microglial-derived factors promoted galectin-9 up-regulation in astrocytes. Astrocyte-derived galectin-9 in turn enhanced microglial TNF production. Similarly, recombinant galectin-9 enhanced poly(I:C)-induced microglial TNF and IL-6 production. Inhibition of Tim-3 did not alter TNF production in mixed glial cultures stimulated with poly(I:C). CONCLUSION:Galectin-9 functions as an astrocyte-microglia communication signal and promotes cytokine production from microglia in a Tim-3 independent manner. Activation of CNS galectin-9 likely modulates neuroinflammatory processes in which TNF and IL-6 contribute to either pathology or reparation. 10.1186/s12974-014-0144-0
    Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation. Watanabe Mitsuru,Masaki Katsuhisa,Yamasaki Ryo,Kawanokuchi Jun,Takeuchi Hideyuki,Matsushita Takuya,Suzumura Akio,Kira Jun-Ichi Scientific reports We previously reported early and extensive loss of astrocytic connexin 43 (Cx43) in acute demyelinating lesions of multiple sclerosis (MS) patients. Because it is widely accepted that autoimmune T cells initiate MS lesions, we hypothesized that infiltrating T cells affect Cx43 expression in astrocytes, which contributes to MS lesion formation. Primary mixed glial cell cultures were prepared from newborn mouse brains, and microglia were isolated by anti-CD11b antibody-conjugated magnetic beads. Next, we prepared astrocyte-rich cultures and astrocyte/microglia-mixed cultures. Treatment of primary mixed glial cell cultures with interferon (IFN) γ, interleukin (IL)-4, or IL-17 showed that only IFNγ or IL-17 at high concentrations reduced Cx43 protein levels. Upon treatment of astrocyte-rich cultures and astrocyte/microglia-mixed cultures with IFNγ, Cx43 mRNA/protein levels and the function of gap junctions were reduced only in astrocyte/microglia-mixed cultures. IFNγ-treated microglia-conditioned media and IL-1β, which was markedly increased in IFNγ-treated microglia-conditioned media, reduced Cx43 protein levels in astrocyte-rich cultures. Finally, we confirmed that Th1 cell-conditioned medium decreased Cx43 protein levels in mixed glial cell cultures. These findings suggest that Th1 cell-derived IFNγ activates microglia to release IL-1β that reduces Cx43 gap junctions in astrocytes. Thus, Th1-dominant inflammatory states disrupt astrocytic intercellular communication and may exacerbate MS. 10.1038/srep38387
    Crosstalk Between Astrocytes and Microglia: An Overview. Matejuk Agata,Ransohoff Richard M Frontiers in immunology Based on discoveries enabled by new technologies and analysis using novel computational tools, neuroscience can be re-conceived in terms of information exchange in dense networks of intercellular connections rather than in the context of individual populations, such as glia or neurons. Cross-talk between neurons and microglia or astrocytes has been addressed, however, the manner in which non-neuronal cells communicate and interact remains less well-understood. We review this intriguing crosstalk among CNS cells, focusing on astrocytes and microglia and how it contributes to brain development and neurodegenerative diseases. The goal of studying these intercellular communications is to promote our ability to combat incurable neurological disorders. 10.3389/fimmu.2020.01416
    Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation during Viral Encephalitis. Chhatbar Chintan,Detje Claudia N,Grabski Elena,Borst Katharina,Spanier Julia,Ghita Luca,Elliott David A,Jordão Marta Joana Costa,Mueller Nora,Sutton James,Prajeeth Chittappen K,Gudi Viktoria,Klein Michael A,Prinz Marco,Bradke Frank,Stangel Martin,Kalinke Ulrich Cell reports In sterile neuroinflammation, a pathological role is proposed for microglia, whereas in viral encephalitis, their function is not entirely clear. Many viruses exploit the odorant system and enter the CNS via the olfactory bulb (OB). Upon intranasal vesicular stomatitis virus instillation, we show an accumulation of activated microglia and monocytes in the OB. Depletion of microglia during encephalitis results in enhanced virus spread and increased lethality. Activation, proliferation, and accumulation of microglia are regulated by type I IFN receptor signaling of neurons and astrocytes, but not of microglia. Morphological analysis of myeloid cells shows that type I IFN receptor signaling of neurons has a stronger impact on the activation of myeloid cells than of astrocytes. Thus, in the infected CNS, the cross talk among neurons, astrocytes, and microglia is critical for full microglia activation and protection from lethal encephalitis. 10.1016/j.celrep.2018.09.003
    Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge. Norden Diana M,Trojanowski Paige J,Villanueva Emmanuel,Navarro Elisa,Godbout Jonathan P Glia Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia, and astrocytes, interpret and propagate inflammatory signals in the brain that influence physiological and behavioral responses. One issue in glial biology is that morphological analysis alone is used to report on glial activation state. Therefore, our objective was to compare behavioral responses after in vivo immune (lipopolysaccharide, LPS) challenge to glial specific mRNA and morphological profiles. Here, LPS challenge induced an immediate but transient sickness response with decreased locomotion and social interaction. Corresponding with active sickness behavior (2-12 h), inflammatory cytokine mRNA expression was elevated in enriched microglia and astrocytes. Although proinflammatory cytokine expression in microglia peaked 2-4 h after LPS, astrocyte cytokine, and chemokine induction was delayed and peaked at 12 h. Morphological alterations in microglia (Iba-1(+)) and astrocytes (GFAP(+)), however, were undetected during this 2-12 h timeframe. Increased Iba-1 immunoreactivity and de-ramified microglia were evident 24 and 48 h after LPS but corresponded to the resolution phase of activation. Morphological alterations in astrocytes were undetected after LPS. Additionally, glial cytokine expression did not correlate with morphology after four repeated LPS injections. In fact, repeated LPS challenge was associated with immune and behavioral tolerance and a less inflammatory microglial profile compared with acute LPS challenge. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba-1 or GFAP immunoreactivity after LPS challenge. 10.1002/glia.22930
    Inflammatory factors and amyloid β-induced microglial polarization promote inflammatory crosstalk with astrocytes. Xie Lushuang,Zhang Ning,Zhang Qun,Li Chenyu,Sandhu Aaron F,Iii George Williams,Lin Sirui,Lv PeiRan,Liu Yi,Wu Qiaofeng,Yu Shuguang Aging The immunological responses are a key pathological factor in Alzheimer's disease (AD). We hypothesized that microglial polarization alters microglia-astrocyte immune interactions in AD. M1 and M2 microglia were isolated from primary rat microglia and were confirmed to secrete pro-inflammatory and anti-inflammatory factors, respectively. Primary rat astrocytes were co-cultured with M1 or M2 microglial medium. M1 microglial medium increased astrocyte production of pro-inflammatory factors (interleukin [IL]-1β, tumor necrosis factor α and IL-6), while M2 microglial medium enhanced astrocyte production of anti-inflammatory factors (IL-4 and IL-10). To analyze the crosstalk between microglia and astrocytes after microglial polarization specifically in AD, we co-cultured astrocytes with medium from microglia treated with amyloid-β (Aβ) alone or in combination with other inflammatory substances. Aβ alone and Aβ combined with lipopolysaccharide/interferon-γ induced pro-inflammatory activity in M1 microglia and astrocytes, whereas IL-4/IL-13 inhibited Aβ-induced pro-inflammatory activity. Nuclear factor κB p65 was upregulated in M1 microglia and pro-inflammatory astrocytes, while Stat6 was upregulated in M2 microglia and anti-inflammatory astrocytes. These results provide direct evidence that microglial polarization governs communication between microglia and astrocytes, and that AD debris alters this crosstalk. 10.18632/aging.103663
    Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime? Liddelow Shane A,Marsh Samuel E,Stevens Beth Trends in immunology Microglia-astrocyte interactions represent a delicate balance affecting neural cell functions in health and disease. Tightly controlled to maintain homeostasis during physiological conditions, rapid and prolonged departures during disease, infection, and following trauma drive multiple outcomes: both beneficial and detrimental. Recent sequencing studies at the bulk and single-cell level in humans and rodents provide new insight into microglia-astrocyte communication in homeostasis and disease. However, the complex changing ways these two cell types functionally interact has been a barrier to understanding disease initiation, progression, and disease mechanisms. Single cell sequencing is providing new insights; however, many questions remain. Here, we discuss how to bridge transcriptional states to specific functions so we can develop therapies to mediate negative effects of altered microglia-astrocyte interactions. 10.1016/j.it.2020.07.006
    Aquaporin-4 mediates communication between astrocyte and microglia: Implications of neuroinflammation in experimental Parkinson's disease. Sun H,Liang R,Yang B,Zhou Y,Liu M,Fang F,Ding J,Fan Y,Hu G Neuroscience Aquaporin-4 (AQP4), a water-selective membrane transport protein, is up-regulated in astrocytes in various inflammatory lesions, including Parkinson disease (PD). However, the exact functional roles of AQP4 in neuroinflammation remain unknown. In the present study, we investigated how AQP4 participates in the neuroinflammation of PD using AQP4 knockout (KO) mice and astrocyte-microglial co-cultures. We found that AQP4 KO mice exhibited increased basal and inducible canonical NF-κB activity, and showed significantly enhanced gliosis (astrocytosis and microgliosis) in chronic MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)/probenecid PD models, companying with the increase in the production of IL-1β and TNF-α in the midbrain. Similarly, AQP4 deficiency augmented the activation of the NF-κB pathway and the production of IL-1β and TNF-α in midbrain astrocyte cultures treated with MPP(+) (1-methyl-4-phenylpyridinium). Furthermore, AQP4 deficiency promoted activation of microglial cells in the co-cultured system. Our data provide the first evidence that AQP4 modulates astrocyte-to-microglia communication in neuroinflammation, although its effect on astrocyte inflammatory activation remains to be explored. 10.1016/j.neuroscience.2016.01.003
    Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion. Chen Tingjun,Lennon Vanda A,Liu Yong U,Bosco Dale B,Li Yujiao,Yi Min-Hee,Zhu Jia,Wei Shihui,Wu Long-Jun The Journal of clinical investigation Neuromyelitis optica (NMO) is a severe inflammatory autoimmune CNS disorder triggered by binding of an IgG autoantibody to the aquaporin 4 (AQP4) water channel on astrocytes. Activation of cytolytic complement has been implicated as the major effector of tissue destruction that secondarily involves myelin. We investigated early precytolytic events in the evolving pathophysiology of NMO in mice by continuously infusing IgG (NMO patient serum-derived or AQP4-specific mouse monoclonal), without exogenous complement, into the spinal subarachnoid space. Motor impairment and sublytic NMO-compatible immunopathology were IgG dose dependent, AQP4 dependent, and, unexpectedly, microglia dependent. In vivo spinal cord imaging revealed a striking physical interaction between microglia and astrocytes that required signaling from astrocytes by the C3a fragment of their upregulated complement C3 protein. Astrocytes remained viable but lost AQP4. Previously unappreciated crosstalk between astrocytes and microglia involving early-activated CNS-intrinsic complement components and microglial C3a receptor signaling appears to be a critical driver of the precytolytic phase in the evolving NMO lesion, including initial motor impairment. Our results indicate that microglia merit consideration as a potential target for NMO therapeutic intervention. 10.1172/JCI134816
    A potential gliovascular mechanism for microglial activation: differential phenotypic switching of microglia by endothelium versus astrocytes. Xing Changhong,Li Wenlu,Deng Wenjun,Ning MingMing,Lo Eng H Journal of neuroinflammation BACKGROUND:Activation of microglia can result in phenotypic and functional diversity. However, the pathways that trigger different states of microglial activation remain to be fully understood. Here, we hypothesized that after injury, astrocytes and endothelium may contribute to a gliovascular switch for microglial activation. METHODS:Astrocytes or cerebral endothelial cells were subjected to oxygen glucose deprivation, then conditioned media were transferred to microglia. The release of TNFα, IL-1β, IL-10, and IGF-1 was measured using ELISA. Surface markers of CD11b, CD45, CD86, and MHC class II were detected by flow cytometry. mRNA expression of iNOS, CD86, CD206, Arginase1, and transcription factors was measured using real-time PCR. Microglial function including migration and phagocytosis was assessed. Dendritogenesis was determined by counting the number of primary dendrites, secondary dendrites, and dendritic ends in the neurons exposed to either endothelial- or astrocyte-activated microglia. RESULTS:Exposure to conditioned media from oxygen-glucose-deprived cerebral endothelial cells or oxygen-glucose-deprived astrocytes activated microglia into different forms. The endothelium converted ramified microglia into amoeboid shapes; increased the release of TNFα, IL-1β, and IL-10; decreased IGF-1; upregulated iNOS expression; and inhibited microglial migration and phagocytosis. In contrast, astrocytes increased microglial production of IGF-1, upregulated CD206 expression, and enhanced microglial phagocytosis. These opposing effects of the endothelium versus astrocyte crosstalk partly mirror potentially deleterious versus potentially beneficial microglial phenotypes. Consistent with this idea, endothelial-activated microglia were neurotoxic, whereas astrocyte-activated microglia did not affect neuronal viability but instead promoted neuronal dendritogenesis. CONCLUSION:These findings provide proof of concept that endothelial cells and astrocytes provide differing signals to microglia that influence their activation states and suggest that a gliovascular switch may be involved in the balance between beneficial versus deleterious microglial properties. 10.1186/s12974-018-1189-2
    Affective Immunology: The Crosstalk Between Microglia and Astrocytes Plays Key Role? Yang Linglin,Zhou Yunxiang,Jia Honglei,Qi Yadong,Tu Sheng,Shao Anwen Frontiers in immunology Emerging evidence demonstrates the critical role of the immune response in the mechanisms relating to mood disorders, such as major depression (MDD) and bipolar disorder (BD). This has cast a spotlight on a specialized branch committed to the research of dynamics of the fine interaction between emotion (or affection) and immune response, which has been termed as "affective immunology." Inflammatory cytokines and gut microbiota are actively involved in affective immunology. Furthermore, abnormalities of the astrocytes and microglia have been observed in mood disorders from both postmortem and molecular imaging studies; however, the underlying mechanisms remain elusive. Notably, the crosstalk between astrocyte and microglia acts as a mutual and pivotal intermediary factor modulating the immune response posed by inflammatory cytokines and gut microbiota. In this study, we propose the "altered astrocyte-microglia crosstalk (AAMC)" hypothesis which suggests that the astrocyte-microglia crosstalk regulates emotional alteration through mediating immune response, and thus, contributing to the development of mood disorders. 10.3389/fimmu.2020.01818
    Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y Receptor Downregulation. Shinozaki Youichi,Shibata Keisuke,Yoshida Keitaro,Shigetomi Eiji,Gachet Christian,Ikenaka Kazuhiro,Tanaka Kenji F,Koizumi Schuichi Cell reports Microglia and astrocytes become reactive following traumatic brain injury (TBI). However, the coordination of this reactivity and its relation to pathophysiology are unclear. Here, we show that microglia transform astrocytes into a neuroprotective phenotype via downregulation of the P2Y purinergic receptor. TBI initially caused microglial activation in the injury core, followed by reactive astrogliosis in the peri-injured region and formation of a neuroprotective astrocyte scar. Equivalent changes to astrocytes were observed in vitro after injury. This change in astrocyte phenotype resulted from P2Y receptor downregulation, mediated by microglia-derived cytokines. In mice, astrocyte-specific P2Y receptor overexpression (Astro-P2YOE) counteracted scar formation, while astrocyte-specific P2Y receptor knockdown (Astro-P2YKD) facilitated scar formation, suggesting critical roles of P2Y receptors in the transformation. Astro-P2YOE and Astro-P2YKD mice showed increased and reduced neuronal damage, respectively. Altogether, our findings indicate that microglia-astrocyte interaction, involving a purinergic signal, is essential for the formation of neuroprotective astrocytes. 10.1016/j.celrep.2017.04.047
    Astrocyte-derived exosomes enriched with miR-873a-5p inhibit neuroinflammation via microglia phenotype modulation after traumatic brain injury. Long Xiaobing,Yao Xiaolong,Jiang Qian,Yang Yiping,He Xuejun,Tian Weidong,Zhao Kai,Zhang Huaqiu Journal of neuroinflammation BACKGROUND:The interaction between astrocytes and microglia plays a vital role in the damage and repair of brain lesions due to traumatic brain injury (TBI). Recent studies have shown that exosomes act as potent mediators involved in intercellular communication. METHODS:In the current study, the expression of inflammatory factors and miR-873a-5p in the lesion area and oedema area was evaluated in 15 patients with traumatic brain injury. Exosomes secreted by astrocytes were detected by immunofluorescence, Western blot and electron microscopy. A mouse model of TBI and an in vitro model of LPS-induced primary microglia were established to study the protective mechanism of exosomes from miR-873a-5p overexpressing in TBI-induced nerve injury. RESULTS:We discovered that exosomes derived from activated astrocytes promote microglial M2 phenotype transformation following TBI. More than 100 miRNAs were detected in these astrocyte-derived exosomes. miR-873a-5p is a major component that was highly expressed in human traumatic brain tissue. Moreover, miR-873a-5p significantly inhibited LPS-induced microglial M1 phenotype transformation and the subsequent inflammation through decreased phosphorylation of ERK and NF-κB p65. This effect also greatly improved the modified neurological severity score (mNSS) and attenuated brain injury in a strictly controlled cortical impact mouse model. CONCLUSIONS:Taken together, our research indicates that miRNAs in the exosomes derived from activated astrocytes play a key role in the astrocyte-microglia interaction. miR-873a-5p, as one of the main components of these astrocyte-derived exosomes, attenuated microglia-mediated neuroinflammation and improved neurological deficits following TBI by inhibiting the NF-κB signalling pathway. These findings suggest a potential role for miR-873a-5p in treating traumatic brain injury. 10.1186/s12974-020-01761-0
    Large-scale death of retinal astrocytes during normal development is non-apoptotic and implemented by microglia. Puñal Vanessa M,Paisley Caitlin E,Brecha Federica S,Lee Monica A,Perelli Robin M,Wang Jingjing,O'Koren Emily G,Ackley Caroline R,Saban Daniel R,Reese Benjamin E,Kay Jeremy N PLoS biology Naturally occurring cell death is a fundamental developmental mechanism for regulating cell numbers and sculpting developing organs. This is particularly true in the nervous system, where large numbers of neurons and oligodendrocytes are eliminated via apoptosis during normal development. Given the profound impact of death upon these two major cell populations, it is surprising that developmental death of another major cell type-the astrocyte-has rarely been studied. It is presently unclear whether astrocytes are subject to significant developmental death, and if so, how it occurs. Here, we address these questions using mouse retinal astrocytes as our model system. We show that the total number of retinal astrocytes declines by over 3-fold during a death period spanning postnatal days 5-14. Surprisingly, these astrocytes do not die by apoptosis, the canonical mechanism underlying the vast majority of developmental cell death. Instead, we find that microglia engulf astrocytes during the death period to promote their developmental removal. Genetic ablation of microglia inhibits astrocyte death, leading to a larger astrocyte population size at the end of the death period. However, astrocyte death is not completely blocked in the absence of microglia, apparently due to the ability of astrocytes to engulf each other. Nevertheless, mice lacking microglia showed significant anatomical changes to the retinal astrocyte network, with functional consequences for the astrocyte-associated vasculature leading to retinal hemorrhage. These results establish a novel modality for naturally occurring cell death and demonstrate its importance for the formation and integrity of the retinal gliovascular network. 10.1371/journal.pbio.3000492
    Astrocytes Stimulate Microglial Proliferation and M2 Polarization In Vitro through Crosstalk between Astrocytes and Microglia. Kim Sumin,Son Youngsook International journal of molecular sciences Microglia are resident immune cells of the central nervous system that act as brain-specific macrophages and are also known to regulate the innate immune functions of astrocytes through secretory molecules. This communication plays an important role in brain functions and homeostasis as well as in neuropathologic disease. In this study, we aimed to elucidate whether astrocytes and microglia could crosstalk to induce microglial polarization and proliferation, which can be further regulated under a microenvironment mimicking that of brain stroke. Microglia in a mixed glial culture showed increased survival and proliferation and were altered to M2 microglia; CD11bGFAP astrocytes resulted in an approximately tenfold increase in microglial cell proliferation after the reconstitution of astrocytes. Furthermore, GM-CSF stimulated microglial proliferation approximately tenfold and induced them to become CCR7 M1 microglia, which have a phenotype that could be suppressed by anti-inflammatory cytokines such as IL-4, IL-10, and substance P. In addition, the astrocytes in the microglial co-culture showed an A2 phenotype; they could be activated to A1 astrocytes by TNF-α and IFN-γ under the stroke-mimicking condition. Altogether, astrocytes in the mixed glial culture stimulated the proliferation of the microglia and M2 polarization, possibly through the acquisition of the A2 phenotype; both could be converted to M1 microglia and A1 astrocytes under the inflammatory stroke-mimicking environment. This study demonstrated that microglia and astrocytes could be polarized to M2 microglia and A2 astrocytes, respectively, through crosstalk in vitro and provides a system with which to explore how microglia and astrocytes may behave in the inflammatory disease milieu after in vivo transplantation. 10.3390/ijms22168800
    Microglia-Astrocyte Crosstalk: An Intimate Molecular Conversation. Jha Mithilesh Kumar,Jo Myungjin,Kim Jae-Hong,Suk Kyoungho The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry Microglia-astrocyte crosstalk has recently been at the forefront of glial research. Emerging evidence illustrates that microglia- and astrocyte-derived signals are the functional determinants for the fates of astrocytes and microglia, respectively. By releasing diverse signaling molecules, both microglia and astrocytes establish autocrine feedback and their bidirectional conversation for a tight reciprocal modulation during central nervous system (CNS) insult or injury. Microglia, the constant sensors of changes in the CNS microenvironment and restorers of tissue homeostasis, not only serve as the primary immune cells of the CNS but also regulate the innate immune functions of astrocytes. Similarly, microglia determine the functions of reactive astrocytes, ranging from neuroprotective to neurotoxic. Conversely, astrocytes through their secreted molecules regulate microglial phenotypes and functions ranging from motility to phagocytosis. Altogether, the microglia-astrocyte crosstalk is fundamental to neuronal functions and dysfunctions. This review discusses the current understanding of the intimate molecular conversation between microglia and astrocytes and outlines its potential implications in CNS health and disease. 10.1177/1073858418783959
    Glutathione -transferases promote proinflammatory astrocyte-microglia communication during brain inflammation. Kano Shin-Ichi,Choi Eric Y,Dohi Eisuke,Agarwal Swati,Chang Daniel J,Wilson Ashley M,Lo Brian D,Rose Indigo V L,Gonzalez Santiago,Imai Takashi,Sawa Akira Science signaling Astrocytes and microglia play critical roles in brain inflammation. Here, we report that glutathione -transferases (GSTs), particularly GSTM1, promote proinflammatory signaling in astrocytes and contribute to astrocyte-mediated microglia activation during brain inflammation. In vivo, astrocyte-specific knockdown of GSTM1 in the prefrontal cortex attenuated microglia activation in brain inflammation induced by systemic injection of lipopolysaccharides (LPS). Knocking down GSTM1 in astrocytes also attenuated LPS-induced production of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) by microglia when the two cell types were cocultured. In astrocytes, GSTM1 was required for the activation of nuclear factor κB (NF-κB) and the production of proinflammatory mediators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and C-C motif chemokine ligand 2 (CCL2), both of which enhance microglia activation. Our study suggests that GSTs play a proinflammatory role in priming astrocytes and enhancing microglia activation in a microglia-astrocyte positive feedback loop during brain inflammation. 10.1126/scisignal.aar2124
    Microglia-Astrocyte Communication via C1q Contributes to Orofacial Neuropathic Pain Associated with Infraorbital Nerve Injury. Asano Sayaka,Hayashi Yoshinori,Iwata Koichi,Okada-Ogawa Akiko,Hitomi Suzuro,Shibuta Ikuko,Imamura Yoshiki,Shinoda Masamichi International journal of molecular sciences Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia-astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain. 10.3390/ijms21186834
    The multifaceted role of astrocytes in regulating myelination. Kıray Hülya,Lindsay Susan L,Hosseinzadeh Sara,Barnett Susan C Experimental neurology Astrocytes are the major glial cell of the central nervous system (CNS), providing both metabolic and physical support to other neural cells. After injury, astrocytes become reactive and express a continuum of phenotypes which may be supportive or inhibitory to CNS repair. This review will focus on the ability of astrocytes to influence myelination in the context of specific secreted factors, cytokines and other neural cell targets within the CNS. In particular, we focus on how astrocytes provide energy and cholesterol to neurons, influence synaptogenesis, affect oligodendrocyte biology and instigate cross-talk between the many cellular components of the CNS. 10.1016/j.expneurol.2016.03.009
    Neuroglia: Functional Paralysis and Reactivity in Alzheimer's Disease and Other Neurodegenerative Pathologies. Verkhratsky Alexei,Zorec Robert,Rodriguez J J,Parpura Vladimir Advances in neurobiology The most notable finding in neurodegenerative diseases is the progressive death of neurones cells. Yet, neuroglial changes can precede and facilitate neuronal loss. This is perhaps expected because astroglial cells maintain the brain homoeostasis, and are responsible for defence and regeneration, so that their malfunction manifested as degeneration or asthenia together with reactivity contribute to pathophysiology. Neuroglia may represent a novel target for therapeutic intervention, be that prevention, slowing progression of or possibly curing neurodegenerative diseases. 10.1007/978-3-319-57193-5_17
    Osmotic Demyelination: From an Oligodendrocyte to an Astrocyte Perspective. Nicaise Charles,Marneffe Catherine,Bouchat Joanna,Gilloteaux Jacques International journal of molecular sciences Osmotic demyelination syndrome (ODS) is a disorder of the central myelin that is often associated with a precipitous rise of serum sodium. Remarkably, while the myelin and oligodendrocytes of specific brain areas degenerate during the disease, neighboring neurons and axons appear unspoiled, and neuroinflammation appears only once demyelination is well established. In addition to blood‒brain barrier breakdown and microglia activation, astrocyte death is among one of the earliest events during ODS pathology. This review will focus on various aspects of biochemical, molecular and cellular aspects of oligodendrocyte and astrocyte changes in ODS-susceptible brain regions, with an emphasis on the crosstalk between those two glial cells. Emerging evidence pointing to the initiating role of astrocytes in region-specific degeneration are discussed. 10.3390/ijms20051124
    Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Silver Jerry,Schwab Martin E,Popovich Phillip G Cold Spring Harbor perspectives in biology Animal studies are now showing the exciting potential to achieve significant functional recovery following central nervous system (CNS) injury by manipulating both the inefficient intracellular growth machinery in neurons, as well as the extracellular barriers, which further limit their regenerative potential. In this review, we have focused on the three major glial cell types: oligodendrocytes, astrocytes, and microglia/macrophages, in addition to some of their precursors, which form major extrinsic barriers to regrowth in the injured CNS. Although axotomized neurons in the CNS have, at best, a limited capacity to regenerate or sprout, there is accumulating evidence that even in the adult and, especially after boosting their growth motor, neurons possess the capacity for considerable circuit reorganization and even lengthy regeneration when these glial obstacles to neuronal regrowth are modified, eliminated, or overcome. 10.1101/cshperspect.a020602
    The story of an exceptional serine protease, tissue-type plasminogen activator (tPA). Hébert M,Lesept F,Vivien D,Macrez R Revue neurologique The only acute treatment of ischemic stroke approved by the health authorities is tissue recombinant plasminogen activator (tPA)-induced thrombolysis. Under physiological conditions, tPA, belonging to the serine protease family, is secreted by endothelial and brain cells (neurons, astrocytes, microglia, oligodendrocytes). Although revascularisation induced by tPA is beneficial during a stroke, research over the past 20 years shows that tPA can also be deleterious for the brain parenchyma. Thus, in this review of the literature, after a brief history on the discovery of tPA, we reviewed current knowledge of mechanisms by which tPA can influence brain function in physiological and pathological conditions. 10.1016/j.neurol.2015.10.002
    Glial Cell: A Potential Target for Cellular and Drug Based Therapy in Various CNS Diseases. Ahmed Shakeeb,Gull Azka,Khuroo Tahir,Aqil Mohd,Sultana Yasmin Current pharmaceutical design Glial cells are integrated part of neurovascular unit of blood brain barrier (BBB). They undergo mitosis and mainly classified as astrocytes, oligodendrocytes, microglia, ependymal cells and nerve glial antigen 2 cells. Being a most versatile glial cell, astrocytes provide structural support to neurons, maintain brain homeostasis, take part in neuronal communication, and perform some housekeeping functions. Oligodendrocytes myelinate the neuronal axons for proper transmission of nerve impulse and microglia are brain immune cells. Multiple sclerosis is a prototype glia mediated disease that manifests demyelination. Fingolimod is already being marketed for this disease, while guanabenz and ibudilast are facing clinical trials. Many researches revealed the role of glial cells in Alzheimer's disease, in which riluzole (a glutamate modulator already in market for amyotrophic lateral sclerosis-ALS) was found to be effective. Q-cells® are glial cell-based therapeutic agent to treat ALS that only produce astrocytes and oligodendrocytes, when transplanted in vivo. hIL13-PE is a gene based therapeutic agent that has been smartly designed for the treatment of glioma. Although for CNS diseases, drugs are available, still it is not easy to extract satisfactory therapeutic effect of most of the drugs due to the presence of BBB. This barrier can be overcome by implanting a drug reservoir in brain parenchyma (wafer), by judicious selection of drug delivery system (nanoparticulate system), or by using an alternative route of administration (intranasal route). This review revolves around cellular and drug based modulation of glial cells to achieve maximum therapeutic benefit for some of the CNS diseases. 10.2174/1381612823666170316124500
    Glial function (and dysfunction) in the normal & ischemic brain. Magaki Shino D,Williams Christopher K,Vinters Harry V Neuropharmacology Astrocytes are the most abundant cell type in the central nervous system (CNS). Once considered to be of fairly homogeneous phenotype throughout the brain and spinal cord, they are now understood to be heterogeneous in both structure and function. They are important in brain functions as diverse as ion and fluid balance in the interstitial space, contributing to integrity of the neurovascular unit (blood-brain barrier), neurotransmitter regulation, metabolism of energy substrates and possibly even axonal regeneration. After ischemic or hemorrhagic brain/spinal cord injury, formation of an astrocytic scar adjacent to the 'lesion' is a characteristic histopathologic feature, and this astrogliosis can be demonstrated by immunohistochemistry, usually using primary antibodies to glial fibrillary acidic protein (GFAP). Astrocytes interact with microglia and oligodendroglia in novel ways that will be discussed in this review. This article is part of the Special Issue entitled 'Cerebral Ischemia'. 10.1016/j.neuropharm.2017.11.009
    The Mitochondria-Derived Peptide Humanin Improves Recovery from Intracerebral Hemorrhage: Implication of Mitochondria Transfer and Microglia Phenotype Change. Jung Joo Eun,Sun Guanghua,Bautista Garrido Jesus,Obertas Lidiya,Mobley Alexis S,Ting Shun-Ming,Zhao Xiurong,Aronowski Jaroslaw The Journal of neuroscience : the official journal of the Society for Neuroscience Astrocytes are an integral component of the neurovascular unit where they act as homeostatic regulators, especially after brain injuries, such as stroke. One process by which astrocytes modulate homeostasis is the release of functional mitochondria (Mt) that are taken up by other cells to improve their function. However, the mechanisms underlying the beneficial effect of Mt transfer are unclear and likely multifactorial. Using a cell culture system, we established that astrocytes release both intact Mt and humanin (HN), a small bioactive peptide normally transcribed from the Mt genome. Further experiments revealed that astrocyte-secreted Mt enter microglia, where they induce HN expression. Similar to the effect of HN alone, incorporation of Mt by microglia (1) upregulated expression of the transcription factor peroxisome proliferator-activated receptor gamma and its target genes (including mitochondrial superoxide dismutase), (2) enhanced phagocytic activity toward red blood cells (an model of hematoma clearance after intracerebral hemorrhage [ICH]), and (3) reduced proinflammatory responses. ICH induction in male mice caused profound HN loss in the affected hemisphere. Intravenously administered HN penetrated perihematoma brain tissue, reduced neurological deficits, and improved hematoma clearance, a function that normally requires microglia/macrophages. This study suggests that astrocytic Mt-derived HN could act as a beneficial secretory factor, including when transported within Mt to microglia, where it promotes a phagocytic/reparative phenotype. These findings also indicate that restoring HN levels in the injured brain could represent a translational target for ICH. These favorable biological responses to HN warrant studies on HN as therapeutic target for ICH. Astrocytes are critical for maintaining brain homeostasis. Here, we demonstrate that astrocytes secrete mitochondria (Mt) and the Mt-genome-encoded, small bioactive peptide humanin (HN). Mt incorporate into microglia, and both Mt and HN promote a "reparative" microglia phenotype characterized by enhanced phagocytosis and reduced proinflammatory responses. Treatment with HN improved outcomes in an animal model of intracerebral hemorrhage, suggesting that this process could have biological relevance to stroke pathogenesis. 10.1523/JNEUROSCI.2212-19.2020
    Expression of SARS-CoV-2-related receptors in cells of the neurovascular unit: implications for HIV-1 infection. Torices Silvia,Cabrera Rosalba,Stangis Michael,Naranjo Oandy,Fattakhov Nikolai,Teglas Timea,Adesse Daniel,Toborek Michal Journal of neuroinflammation BACKGROUND:Neurological complications are common in patients affected by COVID-19 due to the ability of SARS-CoV-2 to infect brains. While the mechanisms of this process are not fully understood, it has been proposed that SARS-CoV-2 can infect the cells of the neurovascular unit (NVU), which form the blood-brain barrier (BBB). The aim of the current study was to analyze the expression pattern of the main SARS-CoV-2 receptors in naïve and HIV-1-infected cells of the NVU in order to elucidate a possible pathway of the virus entry into the brain and a potential modulatory impact of HIV-1 in this process. METHODS:The gene and protein expression profile of ACE2, TMPRSS2, ADAM17, BSG, DPP4, AGTR2, ANPEP, cathepsin B, and cathepsin L was assessed by qPCR, immunoblotting, and immunostaining, respectively. In addition, we investigated if brain endothelial cells can be affected by the exposure to the S1 subunit of the S protein, the domain responsible for the direct binding of SARS-CoV-2 to the ACE2 receptors. RESULTS:The receptors involved in SARS-CoV-2 infection are co-expressed in the cells of the NVU, especially in astrocytes and microglial cells. These receptors are functionally active as exposure of endothelial cells to the SARS CoV-2 S1 protein subunit altered the expression pattern of tight junction proteins, such as claudin-5 and ZO-1. Additionally, HIV-1 infection upregulated ACE2 and TMPRSS2 expression in brain astrocytes and microglia cells. CONCLUSIONS:These findings provide key insight into SARS-CoV-2 recognition by cells of the NVU and may help to develop possible treatment of CNS complications of COVID-19. 10.1186/s12974-021-02210-2