Reactive oxygen species play a role in P2X7 receptor-mediated IL-6 production in spinal astrocytes

Muñoz, Frances M.; Patel, Priya; Gao, Xinghua; Mei, Yixiao; Xia, Jingsheng; Gilels, Sofia; Hu, Huijuan

doi:10.1007/s11302-020-09691-5

Cited by 39 publications

(16 citation statements)

References 70 publications

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“…Classical cytokines released by the P2X7R stimulation are inflammasome/NLRP3-associated IL-1β and IL-18 [24]. However, it has been reported that P2X7R stimulation causes NLRP3-independent IL-6 release in fibroblasts, neurons, astrocytes, microglia, and retinal cells [52][53][54][55][56], e.g., via mechanical stress, ROS signaling and exocytosis. However, IL-1β can upregulate transcription and release of IL-6, and thus, potentiate inflammation [57,58].…”

Section: Discussionmentioning

confidence: 99%

The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells

Magni

Bouazzi

Olmedilla

et al. 2021

Cells

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Pancreatic stellate cells (PSCs) are important pancreatic fibrogenic cells that interact with pancreatic cancer cells to promote the progression of pancreatic ductal adenocarcinoma (PDAC). In the tumor microenvironment (TME), several factors such as cytokines and nucleotides contribute to this interplay. Our aim was to investigate whether there is an interaction between IL-6 and nucleotide signaling, in particular, that mediated by the ATP-sensing P2X7 receptor (P2X7R). Using human cell lines of PSCs and cancer cells, as well as primary PSCs from mice, we show that ATP is released from both PSCs and cancer cells in response to mechanical and metabolic cues that may occur in the TME, and thus activate the P2X7R. Functional studies using P2X7R agonists and inhibitors show that the receptor is involved in PSC proliferation, collagen secretion and IL-6 secretion and it promotes cancer cell migration in a human PSC-cancer cell co-culture. Moreover, conditioned media from P2X7R-stimulated PSCs activated the JAK/STAT3 signaling pathway in cancer cells. The monoclonal antibody inhibiting the IL-6 receptor, Tocilizumab, inhibited this signaling. In conclusion, we show an important mechanism between PSC-cancer cell interaction involving ATP and IL-6, activating P2X7 and IL-6 receptors, respectively, both potential therapeutic targets in PDAC.

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Section: Discussionmentioning

confidence: 99%

The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells

Magni

Bouazzi

Olmedilla

et al. 2021

Cells

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“…Reactive oxygen species (ROS) are another signaling molecule released by macrophages/microglia via P2X7R-induced activation of NADPH oxidase 2 (Apolloni et al, 2014 ; Bartlett et al, 2014 ). Astrocytes were also described to increase ROS production through NADPH oxidase, subsequently leading to IL-6 production (Munoz et al, 2020 ). The above-mentioned class of cytokines and chemokines, such as CCL2 or CCL5, as well as ROS, are neuroinflammatory molecules putting a further burden onto neurons already damaged by various neurodegenerative illnesses such as Alzheimer’s disease (AD; Illes et al, 2019b ), Parkinson’s disease (PD; Carmo et al, 2014 ), amyotrophic lateral sclerosis (Apolloni et al, 2014 ), and multiple sclerosis (MS; Domercq and Matute, 2019 ).…”

Section: Astrocyte-neuron Interaction Via P2x7 Recmentioning

confidence: 99%

Astrocytic and Oligodendrocytic P2X7 Receptors Determine Neuronal Functions in the CNS

Zhao

Tang

Illéš

2021

Front. Mol. Neurosci.

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P2X7 receptors are members of the ATP-gated cationic channel family with a preferential localization at the microglial cells, the resident macrophages of the brain. However, these receptors are also present at neuroglia (astrocytes, oligodendrocytes) although at a considerably lower density. They mediate necrosis/apoptosis by the release of pro-inflammatory cytokines/chemokines, reactive oxygen species (ROS) as well as the excitotoxic (glio)transmitters glutamate and ATP. Besides mediating cell damage i.e., superimposed upon chronic neurodegenerative processes in Alzheimer’s Disease, Parkinson’s Disease, multiple sclerosis, and amyotrophic lateral sclerosis, they may also participate in neuroglial signaling to neurons under conditions of high ATP concentrations during any other form of neuroinflammation/neurodegeneration. It is a pertinent open question whether P2X7Rs are localized on neurons, or whether only neuroglia/microglia possess this receptor-type causing indirect effects by releasing the above-mentioned signaling molecules. We suggest as based on molecular biology and functional evidence that neurons are devoid of P2X7Rs although the existence of neuronal P2X7Rs cannot be excluded with absolute certainty.

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“…The activation of this receptor leads to the formation of a pore in the plasma membrane, which allows potassium to stream out, and calcium to stream in [ 49 , 50 , 51 ]. Activated P2X7R not only promotes the potassium depletion required for inflammasome formation, but also can stimulate generation of oxidative stress via NADPH oxidase activation and it has an adverse impact on mitochondrial function [ 52 , 53 , 54 , 55 ].…”

Section: Mechanisms Involved In the Priming And Activation Of Inflmentioning

confidence: 99%

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

et al. 2020

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Inflammasomes are intracellular protein complexes that form in response to a variety of stress signals and that serve to catalyze the proteolytic conversion of pro-interleukin-1β and pro-interleukin-18 to active interleukin-1β and interleukin-18, central mediators of the inflammatory response; inflammasomes can also promote a type of cell death known as pyroptosis. The NLRP3 inflammasome has received the most study and plays an important pathogenic role in a vast range of pathologies associated with inflammation—including atherosclerosis, myocardial infarction, the complications of diabetes, neurological and autoimmune disorders, dry macular degeneration, gout, and the cytokine storm phase of COVID-19. A consideration of the molecular biology underlying inflammasome priming and activation enables the prediction that a range of nutraceuticals may have clinical potential for suppressing inflammasome activity—antioxidants including phycocyanobilin, phase 2 inducers, melatonin, and N-acetylcysteine, the AMPK activator berberine, glucosamine, zinc, and various nutraceuticals that support generation of hydrogen sulfide. Complex nutraceuticals or functional foods featuring a number of these agents may find utility in the prevention and control of a wide range of medical disorders.

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Reactive oxygen species play a role in P2X7 receptor-mediated IL-6 production in spinal astrocytes

Cited by 39 publications

References 70 publications

The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells

The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells

Astrocytic and Oligodendrocytic P2X7 Receptors Determine Neuronal Functions in the CNS

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

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