Interplay between purinergic signalling and extracellular vesicles in health and disease

Carotti, Valentina; Rigalli, Juan Pablo; Wijst, Jenny; Hoenderop, Joost G. J.

doi:10.1016/j.bcp.2022.115192

Cited by 11 publications

(4 citation statements)

References 149 publications

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“…Several studies have reported that P2X7R stimulation by ATP triggers EV shedding with signi cant change in their size [20,21]. Moreover, EV cargo composition in various cell types, including immune cells and neurons is in uenced by P2X7R stimulation by ATP [22][23][24]82].…”

Section: Discussionmentioning

confidence: 99%

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Neuroinflammatory Responses and Blood–Brain Barrier Injury in Chronic Alcohol Exposure: Role of Purinergic P2X7 Receptor Signaling

Togre,

Melaka,

Bhoj

et al. 2024

Preprint

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Alcohol consumption leads to neuroinflammation and blood‒brain barrier (BBB) damage, resulting in neurological impairment. We previously demonstrated that ethanol-induced disruption of barrier function in human brain endothelial cells was associated with mitochondrial injury, increased ATP and extracellular vesicle (EV) release, and purinergic receptor P2X7R activation. Therefore, we aimed to evaluate the effect of P2X7r blockade on peripheral and neuro-inflammation in EtOH-exposed mice. In a chronic intermittent ethanol (CIE)-exposed mouse model, P2X7R was inhibited by two different methods: Brilliant Blue G (BBG) or gene knockout. We assessed blood ethanol concentration (BEC), plasma P2X7R and P-gp, number of extra-cellular vesicles (EV), serum ATP and EV-ATP levels. Brain microvessel gene expression and EV mtDNA copy numbers were measured by RT2 PCR array and digital PCR, respectively. A RT2 PCR array of brain microvessels revealed significant upregulation of proinflammatory genes involved in apoptosis, vasodilation, and platelet activation in CIE-exposed animals, which were decreased 15–50-fold in BBG-treated CIE-exposed animals. Plasma P-gp levels and serum P2X7R shedding were significantly increased in CIE-exposed animals. Pharmacological or genetic suppression of P2X7R decreased P2X7R shedding to levels equivalent to those in control group. The increase in EV number and EV-ATP content in the CIE-exposed mice was significantly reduced by P2X7R inhibition. CIE mice showed augmented EV-mtDNA copy numbers which were reduced in EVs after P2X7R inhibition or receptor knockout. These observations suggested that P2X7R signaling plays a critical role in ethanol-induced brain injury. Increased eATP, EV-ATP, EV numbers, and EV-mtDNA copy numbers highlight a new mechanism of brain injury during alcohol exposure via P2X7R and biomarkers of such damage. In this study, for the first time, we report the in vivo involvement of P2X7R signaling in CIE-induced brain injury.

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Section: Discussionmentioning

confidence: 99%

“…Extracellular ATP stimulates P2X7R, which triggers extracellular vesicle (EV) shedding [20,21]. EVs are cargo-carrying cell-derived vesicles which can communicate between originating and recipient cells.…”

Section: Introductionmentioning

confidence: 99%

Neuroinflammatory Responses and Blood–Brain Barrier Injury in Chronic Alcohol Exposure: Role of Purinergic P2X7 Receptor Signaling

Togre,

Melaka,

Bhoj

et al. 2024

Preprint

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“…In this review, we will exclusively focus on the immunoregulatory role of EVs containing molecules of the purinergic pathway. For the interested reader, excellent reviews covering the role of EVs in the immune system ( 2 ) and the interplay between purinergic signaling and EVs ( 3 ) have been recently published.…”

Section: Introductionmentioning

confidence: 99%

Purinergic enzymes on extracellular vesicles: immune modulation on the go

Winzer,

Nguyen,

Schoppmeier

et al. 2024

Front. Immunol.

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An increase in the extracellular concentration of ATP as a consequence of cellular stress or cell death results in the activation of immune cells. To prevent inflammation, extracellular ATP is rapidly metabolized to adenosine, which deploys an anti-inflammatory signaling cascade upon binding to P1 receptors on immune cells. The ectonucleotidases necessary for the degradation of ATP and generation of adenosine are present on the cell membrane of many immune cells, and their expression is tightly regulated under conditions of inflammation. The discovery that extracellular vesicles (EVs) carry purinergic enzyme activity has brought forward the concept of EVs as a new player in immune regulation. Adenosine-generating EVs derived from cancer cells suppress the anti-tumor response, while EVs derived from immune or mesenchymal stem cells contribute to the restoration of homeostasis after infection. Here we will review the existing knowledge on EVs containing purinergic enzymes and molecules, and discuss the relevance of these EVs in immune modulation and their potential for therapy.

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“…It is highly expressed by cells of the innate immune system, especially macrophages [ 1 ], dendritic cells [ 2 ], mast cells [ 3 ], and microglia [ 4 ], where it promotes inflammasome formation and the release of inflammatory cytokines [ 5 , 6 , 7 ]. P2X 7 R is also present in adaptive immune cells (T cells), where it regulates cell development and function [ 8 ], and in many other cell types [ 9 ] including nervous system cells [ 10 , 11 ], epithelial and endothelial cells [ 12 , 13 ], bone cells [ 14 ], fibroblasts [ 15 ], and smooth muscle cells [ 16 ], as well as in tumor cells, where its expression often correlates with a worse diagnosis [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

P2X7 Receptor and Extracellular Vesicle Release

Golia

Gabrielli

Verderio

2023

IJMS

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Extensive evidence indicates that the activation of the P2X7 receptor (P2X7R), an ATP-gated ion channel highly expressed in immune and brain cells, is strictly associated with the release of extracellular vesicles. Through this process, P2X7R-expressing cells regulate non-classical protein secretion and transfer bioactive components to other cells, including misfolded proteins, participating in inflammatory and neurodegenerative diseases. In this review, we summarize and discuss the studies addressing the impact of P2X7R activation on extracellular vesicle release and their activities.

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Interplay between purinergic signalling and extracellular vesicles in health and disease

Cited by 11 publications

References 149 publications

Neuroinflammatory Responses and Blood–Brain Barrier Injury in Chronic Alcohol Exposure: Role of Purinergic P2X7 Receptor Signaling

Neuroinflammatory Responses and Blood–Brain Barrier Injury in Chronic Alcohol Exposure: Role of Purinergic P2X7 Receptor Signaling

Purinergic enzymes on extracellular vesicles: immune modulation on the go

P2X7 Receptor and Extracellular Vesicle Release

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