Morphine‐mediated release of miR‐138 in astrocyte‐derived extracellular vesicles promotes microglial activation

Liao, Ke; Niu, Fang; Hu, Guoku; Lü, Yang; Dallon, Blake W.; Villarreal, Delaney; Buch, Shilpa

doi:10.1002/jev2.12027

Cited by 36 publications

(21 citation statements)

References 91 publications

(121 reference statements)

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“…Herein we sought to determine whether ADEVs released from morphine-stimulated HPAs could also contain the amyloid cargoes. Astrocytes have been shown to produce considerable amounts of EVs [ 59 ] and were thus chosen for this study. For this we first isolated and characterized ADEVs from conditioned media of HPAs, using a differential ultracentrifugation procedure ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Astrocytes & Astrocyte derived Extracellular Vesicles in Morphine Induced Amyloidopathy: Implications for Cognitive Deficits in Opiate Abusers

Sil¹,

Singh²,

Chemparathy³

et al. 2021

Aging and disease

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While opiates like morphine play a major role in the pharmacotherapy for the control of pain associated with various diseases, paradoxically, their long-term use is associated with cognitive impairments. Furthermore, morphine administration has been shown to result in neuronal synaptodendritic injury in rodent brains, leading to neurodegeneration. We recently reported the role of astrocytes as contributors of amyloidosis associated with HIV-associated neurological disorders. Herein we hypothesize that morphine could induce astrocytic amyloidosis, which, in turn, could be disseminated to various regions in the brain by astrocyte-derived EVs (ADEVs). In this study we demonstrate brain region-specific up-regulation of astrocytic amyloids in morphine dependendent rhesus macaques. In addition, herein we also demonstrate increased expression of β-site cleaving enzyme (BACE1), APP, and Aβ in human primary astrocytes (HPAs) exposed to morphine. Mechanisms involved in this process included the up-regulation of hypoxia-inducible factor (HIF-1α), its translocation and binding to the promoter of BACE1, leading to increased BACE1 activity and, generation of Aβ 1-42. Gene silencing approaches confirmed the regulatory role of HIF-1α in BACE1 mediated amyloidosis leading to astrocyte activation and neuroinflammation. We next sought to assess whether morphine-stimulated ADEVs could carry amyloid cargoes. Results showed that morphine exposure induced the release of morphine-ADEVs, carrying amyloids. Interestingly, silencing HIF-1α in astrocytes not only reduced the numbers of ADEV released, but also the packaging of amyloid cargos in the ADEVs. These findings were further validated in brain derived EVs (BEVs) isolated from macaques, wherein it was shown that BEVs from morphine-dependent macaques, carried varieties of amyloid cargoes including the cytokine IL-1β. This is the first report implicating the role of HIF-1α-BACE1 axis in morphine-mediated induction of astrocytic amyloidosis, leading, in turn, to neuroinflammation and release of the amyloid cargoes via ADEVs. These findings set the groundwork for the future development of therapeutic strategies for targeting cognitive deficits in chronic opiate users.

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Section: Resultsmentioning

confidence: 99%

Astrocytes & Astrocyte derived Extracellular Vesicles in Morphine Induced Amyloidopathy: Implications for Cognitive Deficits in Opiate Abusers

Sil¹,

Singh²,

Chemparathy³

et al. 2021

Aging and disease

Self Cite

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“…Strikingly, IL1‐β‐induced EVs rapidly entered into the peripheral circulation and promoted the recruitment of peripheral leukocytes 34 . Morphine treatment of astrocytes induced the release of miR‐138 in EVs promoting microglia activation via TLR7 signaling implicated in neuroinflammation observed in opioid abusers 35 . Furthermore, astrocyte‐derived small EVs appear to facilitate neuroprotection against cell insult (reviewed in Ref.…”

Section: Cellular Routes Of Neural Evsmentioning

confidence: 99%

Extracellular Vesicles in neural cell interaction and CNS homeostasis

et al. 2021

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Central nervous system (CNS) homeostasis critically depends on the interaction between neurons and glia cells. Extracellular vesicles (EVs) recently emerged as versatile messengers in CNS cell communication. EVs are released by neurons and glia in activity-dependent manner and address multiple target cells within and outside the nervous system. Here, we summarize the recent advances in understanding the physiological roles of EVs in the nervous system and their ability to deliver signals across the CNS barriers. In addition to the disposal of cellular components via EVs and clearance by phagocytic cells, EVs are involved in plasticity-associated processes, mediate trophic support and neuroprotection, promote axonal maintenance, and modulate neuroinflammation. While individual functional components of the EV cargo are becoming progressively identified, the role of neural EVs as compound multimodal signaling entities remains to be elucidated. Novel transgenic models and imaging technologies allow EVtracking in vivo and provide further insight into EV targeting and their mode of action. Overall, EVs represent key players in the maintenance of CNS homeostasis essential for the life-long performance of neural networks and thus provide a wide spectrum of biomedical applications.

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“…When injury occurs, activated microglia develop enlarged cell bodies, shortened processes, and their cell morphology becomes amoeba-like; they also adopt a phagocytic function ( 26 , 32 ). As the immune cells of the CNS, the morphological changes of microglia are closely related to the functions ( 33 , 34 ). We examined four key morphological parameters to evaluate changes in microglial morphology following SAH, including fractal dimension, density, area, and perimeter.…”

Section: Discussionmentioning

confidence: 99%

Activation of RARα Receptor Attenuates Neuroinflammation After SAH via Promoting M1-to-M2 Phenotypic Polarization of Microglia and Regulating Mafb/Msr1/PI3K-Akt/NF-κB Pathway

Tian

Liu

et al. 2022

Front. Immunol.

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Background and PurposeSubarachnoid hemorrhage (SAH) is a life-threatening subtype of stroke with high rates of mortality. In the early stages of SAH, neuroinflammation is one of the important mechanisms leading to brain injury after SAH. In various central nervous system diseases, activation of RARα receptor has been proven to demonstrate neuroprotective effects. This study aimed to investigate the anti-inflammatory effects of RARα receptor activation after SAH.MethodsInternal carotid artery puncture method used to established SAH model in Sprague-Dawley rats. The RARα specific agonist Am80 was injected intraperitoneally 1 hour after SAH. AGN196996 (specific RARα inhibitor), Msr1 siRNA and LY294002 (PI3K-Akt inhibitor) were administered via the lateral ventricle before SAH. Evaluation SAH grade, neurological function score, blood-brain barrier permeability. BV2 cells and SH-SY5Y cells were co-cultured and stimulated by oxyhemoglobin to establish an in vitro model of SAH. RT-PCR, Western blotting, and immunofluorescence staining were used to investigate pathway-related proteins, microglia activation and inflammatory response. Results: The expression of RARα, Mafb, and Msr1 increased in rat brain tissue after SAH. Activation of the RARα receptor with Am80 improved neurological deficits and attenuated brain edema, blood brain barrier permeability. Am80 increased the expression of Mafb and Msr1, and reduced neuroinflammation by enhancing the phosphorylation of Akt and by inhibiting the phosphorylation of NF-κB. AGN196996, Msr1 siRNA, and LY294002 reversed the therapeutic effects of Am80 by reducing the expression of Msr1 and the phosphorylation of Akt. In vitro model of SAH, Am80 promoted M1-to-M2 phenotypic polarization in microglia and suppressed the nuclear transcription of NF-κB.ConclusionActivation of the RARα receptor attenuated neuroinflammation by promoting M1-to-M2 phenotypic polarization in microglia and regulating the Mafb/Msr1/PI3K-Akt/NF-κB pathway. RARα might serve as a potential target for SAH therapy.

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Morphine‐mediated release of miR‐138 in astrocyte‐derived extracellular vesicles promotes microglial activation

Cited by 36 publications

References 91 publications

Astrocytes & Astrocyte derived Extracellular Vesicles in Morphine Induced Amyloidopathy: Implications for Cognitive Deficits in Opiate Abusers

Astrocytes & Astrocyte derived Extracellular Vesicles in Morphine Induced Amyloidopathy: Implications for Cognitive Deficits in Opiate Abusers

Extracellular Vesicles in neural cell interaction and CNS homeostasis

Activation of RARα Receptor Attenuates Neuroinflammation After SAH via Promoting M1-to-M2 Phenotypic Polarization of Microglia and Regulating Mafb/Msr1/PI3K-Akt/NF-κB Pathway

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