Microglia-Astrocyte Crosstalk: An Intimate Molecular Conversation

Jha, Mithilesh Kumar; Jo, Myungjin; Kim, Jae Hong; Suk, Kyoungho

doi:10.1177/1073858418783959

Cited by 443 publications

(391 citation statements)

References 103 publications

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“…Astrocytes via their secreted factors are known to modulate microglial phenotypes and functions like phagocytosis and motility (Jha, Jo, Kim, & Suk, ). Based on the increased secretion of S1P from astrocytes, and the well‐known role of S1P in inflammation, we hypothesized increased activation of microglia in SGPL1 fl/fl/Nes mice.…”

Section: Resultsmentioning

confidence: 99%

“…F I G U R E 1 Increased S1P levels in primary astrocytes but not microglia of SGPL1 fl/fl/Nes mice. The expression of S1P-lyase (SGPL1) was assessed in primary astrocyte (a) and microglial cultures ( Kim, & Suk, 2018). Based on the increased secretion of S1P from astrocytes, and the well-known role of S1P in inflammation, we hypothesized increased activation of microglia in SGPL1 fl/fl/Nes mice.…”

Section: Resultsmentioning

confidence: 99%

“…Emerging research has highlighted the bidirectional communication between microglia and astrocytes as a fundamental aspect of CNS responses to injuries and pathologies (Jha et al, 2018). Astrocyte signal galectin-9 has earlier been shown to potentiate TNF secretion from microglia (Steelman & Li, 2014) and astrocyte secreted cytokines are known to induce transformation from ameboid to ramified morphology in microglia (Schilling, Nitsch, Heinemann, Haas, & Eder, 2001).…”

Section: Discussionmentioning

confidence: 99%

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Neural sphingosine 1‐phosphate accumulation activates microglia and links impaired autophagy and inflammation

Indulekha

Alam

Surendar

et al. 2019

Glia

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Microglia mediated responses to neuronal damage in the form of neuroinflammation is a common thread propagating neuropathology. In this study, we investigated the microglial alterations occurring as a result of sphingosine 1‐phosphate (S1P) accumulation in neural cells. We evidenced increased microglial activation in the brains of neural S1P‐lyase (SGPL1) ablated mice (SGPL1fl/fl/Nes) as shown by an activated and deramified morphology and increased activation markers on microglia. In addition, an increase of pro‐inflammatory cytokines in sorted and primary cultured microglia generated from SGPL1 deficient mice was noticed. Further, we assessed autophagy, one of the major mechanisms in the brain that keeps inflammation in check. Indeed, microglial inflammation was accompanied by defective microglial autophagy in SGPL1 ablated mice. Rescuing autophagy by treatment with rapamycin was sufficient to decrease interleukin 6 (IL‐6) but not tumor necrosis factor (TNF) secretion in cultured microglia. Rapamycin mediated decrease of IL‐6 secretion suggests a particular mechanistic target of rapamycin (mTOR)‐IL‐6 link and appeared to be microglia specific. Using pharmacological inhibitors of the major receptors of S1P expressed in the microglia, we identified S1P receptor 2 (S1PR2) as the mediator of both impaired autophagy and proinflammatory effects. In line with these results, the addition of exogenous S1P to BV2 microglial cells showed similar effects as those observed in the genetic knock out of SGPL1 in the neural cells. In summary, we show a novel role of the S1P‐S1PR2 axis in the microglia of mice with neural‐targeted SGPL1 ablation and in BV2 microglial cell line exogenously treated with S1P.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Neural sphingosine 1‐phosphate accumulation activates microglia and links impaired autophagy and inflammation

Indulekha

Alam

Surendar

et al. 2019

Glia

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“…1-3), we asked what are the physiological consequences of such microglia-astrocyte crosstalk in the pathophysiology of TBI. As a first approach, we investigated the alterations in the blood-brain barrier (BBB) integrity, which is highly regulated by astrocytes and dramatically disrupted following an acute TBI (2,12,31,32).…”

Section: Figurementioning

confidence: 99%

“…In addition, microglia activation determines the fate of astrocytes by releasing a plethora of signaling factors that induce reactive astrogliosis and regulate astrocytic immune reactions (10,11). On the other hand, activated astrocytes-derived factors also trigger microglial activation and control their cellular functions (12). In this way, microglia and astrocytes establish a bidirectional communication that is determinant for the fate of both cell types as well as for the function of neuronal networks.…”

Section: Introductionmentioning

confidence: 99%

TLR4-pathway impairs synaptic number and cerebrovascular functions through astrocyte activation following traumatic brain injury

Rosa

Farré‐Alins

Ortega

et al. 2020

Preprint

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Activation of microglia and astrocytes contributes to synaptic remodeling, tissue repair and neuronal survival following traumatic brain injury (TBI). However, the consequences of the interaction between both glial cell types in rewiring neuronal networks and repairing brain functions remains poorly understood. Here, we explored how microglia-induced astrocyte activation modified synapses and cerebrovascular integrity following TBI. Calcium imaging experiments from brain slices revealed increased number of active astrocytes responding with spontaneous Ca 2+ events surrounding the injury at 1 d.a.i. These changes correlated with an increase in astrocytic GFAP-reactivity and microglia activation. Blocking microglia activation with the TLR4-blocker TAK242 reduced both the number of active and reactive astrocytes, suggesting a role for microglia in mediating astrocyte excitability. To determine the physiological consequences of microglia-induced astrocyte activation, we first quantified the number of synaptic puncta in TBI-mice treated with the TLR4-blocker. PSD-95/VGlut-1 staining showed that TAK-treatment reduced by half the synaptic loss observed in TBI-mice. Similar effects were also observed in the blood-brain barrier (BBB) integrity, in which blockage of microglia decreased Evans Blue extravasation, an indicative of preserved BBB. The acute effects of microglia inhibition on synapses and BBB were not observed in IP 3 R2 -/mice, indicating that the microglial effects depend on the subsequent astrocyte activation. In addition, acute TBI increases the release of the astrocytic-protein thrombospondin-1 (TSP-1) that seems to be necessary to modulate synaptic puncta in a sub-acute phase. Together, our data demonstrate that microglia-toastrocyte communication plays a crucial role in the pathophysiology of TBI and that its inhibition prevents the synaptic loss and BBB damage accelerating the recovery/repair of damaged tissue.Overall, our data indicates that targeting the microglia-astrocyte crosstalk might represent a therapeutic potential in CNS injuries and disorders.

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Controlled Activation of TRPV1 Channels on Microglia to Boost Their Autophagy for Clearance of Alpha‐Synuclein and Enhance Therapy of Parkinson's Disease

et al. 2022

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α-syn can spread through the adjacent neurons in anatomically connected brain regions, and serve as seeds to induce the aggregation and deposition of α-syn monomers, [3][4][5] which could increase oxidative stress, depolarize mitochondria, disturb protein clearance, and alter the cytoskeleton, leading to neuronal damage and the progression of PD. [6] The accumulation of α-syn in the midbrain plays a key role in the pathogenesis of PD, [7] and how to eliminate α-syn aggregates is crucial for the success of treatment.In the brain, microglia as an important type of innate immune cells play vital roles in supporting brain development, monitoring the neuronal activity, regulating learning and memory capabilities, and act as local phagocytes and damage sensors in the brain parenchyma. [8,9] They can phagocytose and degrade misfolded and aggregated proteins (such as α-syn) to prevent the formation of LBs. [10,11] Recent studies suggest that microglia ingested and degraded neuron-released α-syn aggregates through selective autophagy, which was mediated by Toll-like receptor (TLR) 2, TLR4-NF-κB, and LC3-associated endocytosis (LANDO). [12][13][14] Further studies show that the production of inflammatory factors and neurodegeneration would proceed unchecked in the absence of LANDO. [15,16] There are many ways to activate the autophagy of microglia, including use of rapamycin as an autophagy inducer, [17] capsaicin (CAP) as an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), [18] and P2×7 receptors (P2×7Rs) as the members of the family of ionotropic ATP-gated receptors, [19] of which targeting their surface rich TRPV1 receptors is the most promising approach. [20] TRPV1 receptors are temperature-sensitive cationic channels, [21,22] which have been demonstrated to be an effective target for the treatment of neurodegenerative diseases by using CAP as stimuli. [23,24] However, the direct use of CAP as TRPV1 agonist in clinical practice is limited by its toxic side effects. [25] In particular, the uncontrollable continuous stimulation by CAP can cause the influx of excessive calcium ions (Ca 2+ ) into microglia to damage mitochondria and even cause apoptosis, it is crucial to control the influx of Ca 2+ under stimulation. [26] In addition, it is very difficult to modulate TRPV1 signal transduction by using CAP due to the lack of its targeting capability, and Parkinson's disease (PD) is characterized with accumulation of Lewy bodies with a major component of fibrillar alpha-synuclein (α-syn). Herein, boosting PD therapeutic efficacy by enhancing the autophagy of microglia to phagocytose and degrade α-syn via controlled opening of their surface TRPV1 channels with rationally designed photothermal nanoagent is reported. The Cu 2−x Se-anti-TRPV1 nanoparticles (CS-AT NPs) are fabricated to target the microglia and open their surface TRPV1 channels under the second near infrared (NIR-II) laser irradiation to cause influx of Ca 2+ to activate ATG5 and Ca 2+ /CaMKK2/AMPK/mTOR signaling pathway, which promote phagocy...

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Microglia-Astrocyte Crosstalk: An Intimate Molecular Conversation

Cited by 443 publications

References 103 publications

Neural sphingosine 1‐phosphate accumulation activates microglia and links impaired autophagy and inflammation

Neural sphingosine 1‐phosphate accumulation activates microglia and links impaired autophagy and inflammation

TLR4-pathway impairs synaptic number and cerebrovascular functions through astrocyte activation following traumatic brain injury

Controlled Activation of TRPV1 Channels on Microglia to Boost Their Autophagy for Clearance of Alpha‐Synuclein and Enhance Therapy of Parkinson's Disease

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