Mesenchymal stem cells-derived IL-6 activates AMPK/mTOR signaling to inhibit the proliferation of reactive astrocytes induced by hypoxic-ischemic brain damage

He, Mulan; Shi, Xia; Yang, Miao; Yang, Ting; Li, Tingyu; Chen, Jie

doi:10.1016/j.expneurol.2018.09.006

Cited by 46 publications

(27 citation statements)

References 67 publications

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“…Under the paradigm of sublethal oxygen/glucose deprivation with subsequent reoxygenation, a reactive induction of astrocytic proliferation after reoxygenation is observed (38,39). The experimental conditions of this study differed in that the glucose/oxygen deprivation applied was permanent and no reoxygenation was performed to specifically measure the amount of cell death occurring under hypoxia and glucose deprivation.…”

Section: Discussionmentioning

confidence: 99%

AMPK activation protects astrocytes from hypoxia‑induced cell death

Strecker

Luger

et al. 2020

Int J Mol Med

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Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a major cellular energy sensor that is activated by an increase in the AMP/adenosine triphosphate (ATP) ratio. This causes the initiation of adaptive cellular programs, leading to the inhibition of anabolic pathways and increasing ATP synthesis. AMPK indirectly inhibits mammalian target of rapamycin (mTOR) complex 1 (mTORc1), a serine/threonine kinase and central regulator of cell growth and metabolism, which integrates various growth inhibitory signals, such as the depletion of glucose, amino acids, ATP and oxygen. While neuroprotective approaches by definition focus on neurons, that are more sensitive under cell stress conditions, astrocytes play an important role in the cerebral energy homeostasis during ischemia. Therefore, the protection of astrocytic cells or other glial cells may contribute to the preservation of neuronal integrity and function. In the present study, it was thus hypothesized that a preventive induction of energy deprivation-activated signaling pathways via AMPK may protect astrocytes from hypoxia and glucose deprivation. Hypoxia-induced cell death was measured in a paradigm of hypoxia and partial glucose deprivation in vitro in the immortalized human astrocytic cell line SVG. Both the glycolysis inhibitor 2-deoxy-d-glucose (2dG) and the AMPK activator A-769662 induced the phosphorylation of AMPK, resulting in mTORc1 inhibition, as evidenced by a decrease in the phosphorylation of the target ribosomal protein S6 (RPS6). Treatment with both 2dG and A-769662 also decreased glucose consumption and lactate production. Furthermore, A-769662, but not 2dG induced an increase in oxygen consumption, possibly indicating a more efficient glucose utilization through oxidative phosphorylation. Hypoxia-induced cell death was profoundly reduced by treatment with 2dG or A-769662. On the whole, the findings of the present study demonstrate, that AMPK activation via 2dG or A-769662 protects astrocytes under hypoxic and glucose-depleted conditions.

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Section: Discussionmentioning

confidence: 99%

AMPK activation protects astrocytes from hypoxia‑induced cell death

Strecker

Luger

et al. 2020

Int J Mol Med

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“…The activated CD8 lymphocytes increase GFAP expression in NPCs and induce their differentiation via interferon-γ (Hu, Rotschafer, Lokensgard, & Cheeran, 2014). By contrast, chronic unpredictable mild stress-induced depression is associated with GFAP reduction in relation to the increase in TNF-α, interferon-γ, IL-1β, and IL-17 concentrations (He et al, 2019).…”

Section: Inflammationmentioning

confidence: 99%

“…The activated CD8 lymphocytes increase GFAP expression in NPCs and induce their differentiation via interferon‐γ (Hu, Rotschafer, Lokensgard, & Cheeran, ). By contrast, chronic unpredictable mild stress‐induced depression is associated with GFAP reduction in relation to the increase in TNF‐α, interferon‐γ, IL‐1β, and IL‐17 concentrations (He et al, ). It is also reported that the HIV‐1 viral envelope glycoprotein gp120 directly inhibits the phosphorylation of GFAP and that GFAP levels decrease in response to chronic infection with HIV‐1 (Levi, Patrizio, Bernardo, Petrucci, & Agresti, ).…”

Section: Gfap and Neurological Diseasesmentioning

confidence: 99%

“…On the one hand, neuroinflammation can dramatically change GFAP expression. For instance, IL‐6 secreted by mesenchymal stem cells plays an antiapoptotic role in injured astrocytes and partly promotes functional recovery in neonatal rats after hypoxic–ischemic brain damage (He et al, ). Moreover, chronic neuroinflammation of experimental herpes simplex encephalitis in mice is dominated by brain‐infiltrating activated CD8 lymphocytes.…”

Section: Gfap and Neurological Diseasesmentioning

confidence: 99%

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Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

Liu

et al. 2019

Glia

103

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Glial fibrillary acidic protein (GFAP), a type III intermediate filament, is a marker of mature astrocytes. The expression of GFAP gene is regulated by many transcription factors (TFs), mainly Janus kinase‐2/signal transducer and activator of transcription 3 cascade and nuclear factor κ‐light‐chain‐enhancer of activated B cell signaling. GFAP expression is also modulated by protein kinase and other signaling molecules that are elicited by neuronal activity and hormones. Abnormal expression of GFAP proteins occurs in neuroinflammation, neurodegeneration, brain edema‐eliciting diseases, traumatic brain injury, psychiatric disorders and others. GFAP, mainly in α‐isoform, is the major component of cytoskeleton and the scaffold of astrocytes, which is essential for the maintenance of astrocytic structure and shape. GFAP also has highly morphological plasticity because of its quick changes in assembling and polymerizing states in response to environmental challenges. This plasticity and its corresponding cellular morphological changes endow astrocytes the functions of physical barrier between adjacent neurons and stabilizer of extracellular environment. Moreover, GFAP colocalizes and even molecularly associates with many functional molecules. This feature allows GFAP to function as a platform for direct interactions between different molecules. Last, GFAP involves transportation and localization of other functional proteins and thus serves as a protein transport guide in astrocytes. This guiding role of GFAP involves an elastic retraction and extension cytoskeletal network that couples with GFAP reassembling, transporting, and membrane protein recycling machinery. This paper reviews our current understanding of the expression and functions of GFAP as well as their regulation.

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“…Furthermore, significantly increased mTOR activity has been revealed upon IL-6 stimulation. 109 (Figure 2).…”

Section: Sar S -Cov2 and Hepati C S Te Atos Ismentioning

confidence: 99%

Pathophysiological mechanisms of liver injury in COVID‐19

Nardo

Schneeweiss-Gleixner

Bakail

et al. 2020

Liver International

333

364

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, the outbreak of coronavirus disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV) 2 (SARS-CoV-2), has led within a few months to a major global health and economic crisis. As of October 2020, more than 40 million confirmed cases have been reported worldwide, with nearly 1 million deaths, affecting 189 countries. 1 The respiratory tract is considered the main target of SARS-CoV-2 infection and a small subset of infected individuals becomes severely ill and may develop acute respiratory distress syndrome (ARDS) with potentially fatal outcome. 2 More recently, systemic features of the disease with the involvement of organs outside the respiratory tract, including the liver and gastrointestinal tract are receiving increasing attention, indicating that COVID-19 may be considered as a systemic infectious and inflammatory disease. 3-7 Although closely related to other Corona virus (CoV) family members SARS-CoV and MERS-CoV (Middle East Respiratory Syndrome CoV), infections with the new SARS-CoV-2 exhibit a different pathological pattern and the mechanistic link between CoVs-induced molecular pathophysiological changes and clinical manifestations remains incompletely understood.

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Mesenchymal stem cells-derived IL-6 activates AMPK/mTOR signaling to inhibit the proliferation of reactive astrocytes induced by hypoxic-ischemic brain damage

Cited by 46 publications

References 67 publications

AMPK activation protects astrocytes from hypoxia‑induced cell death

AMPK activation protects astrocytes from hypoxia‑induced cell death

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

Pathophysiological mechanisms of liver injury in COVID‐19

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