Microvesicles in Health and Disease

Inal, Jameel M.; Ansa-Addo, Ephraim; Stratton, Dan; Kholia, Sharad; Antwi‐Baffour, Samuel; Jorfi, Samireh; Lange, Sigrun

doi:10.1007/s00005-012-0165-2

Cited by 60 publications

(64 citation statements)

References 141 publications

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“…Microvesicles (MVs) are small vesicles derived from the plasma membrane of eukaryotic cells [1,2]. MVs are gaining momenCorrespondence: Dr. Davide Ferrari e-mail: dfr@unife.it tum as they have been isolated in tumors, infectious and autoimmune diseases, and a role in delivery different messages to the cells has also been demonstrated [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

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IL‐18 associates to microvesicles shed from human macrophages by a LPS/TLR‐4 independent mechanism in response to P2X receptor stimulation

et al. 2012

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Extracellular ATP, released upon microbial infection, cell damage, or inflammation, acts as an alert signal toward immune cells by activating P2 receptors. The nucleotide causes microvesicle (MV) shedding from immune and nonimmune cells. Here, we show that IL-18 associates with MVs shed by human ex vivo macrophages upon P2X receptor stimulation.MV shedding was potently induced by ATP and by the P2X7 agonist 3 -benzoylbenzoyl adenosine 5 -triphosphate, while it was greatly reduced by P2X irreversible inhibitoroxidized ATP and by the specific P2X7 inhibitors KN-62, A-740003, and A-438079. Peculiarly, the P2X7 subtype was highly present in the MVs, while on the contrary the P2X3 and P2X4 subtypes were almost absent. The Ca 2+ ionophore A23187 mimicked the effect of 3 -benzoylbenzoyl adenosine 5 -triphosphate suggesting that an intracellular Ca 2+ increase was sufficient to evoke MV shedding. Caspase inhibitors Ac-YVAD-CMK or Z-YVAD-CMK did not block the cleavage of MV-associated pro-IL-18. Pro-IL-18 formation in macrophages did not require pretreatment of cells with LPS, as the procytokine was already present in unprimed macrophages and did not decrease by incubating cells with the LPS-binding antibiotic polymyxin B nor with the TLR-4 intracellular inhibitor CLI-095. These data reveal a nucleotide-based mechanism responsible for the shedding of MV to which IL-18 is associated.Keywords: Extracellular ATP r Human macrophages r IL-18 r P2 receptors r P2X7 Supporting Information available online IntroductionMicrovesicles (MVs) are small vesicles derived from the plasma membrane of eukaryotic cells [1,2]. MVs are gaining momenCorrespondence: Dr. Davide Ferrari e-mail: dfr@unife.it tum as they have been isolated in tumors, infectious and autoimmune diseases, and a role in delivery different messages to the cells has also been demonstrated [2][3][4]. They can transport and deliver proteins, enzymes, mRNA, or microRNA. Recent * These authors contributed equally to this work.C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 3334-3345 Innate immunity 3335 observations have shown that MVs shed by mesenchymal stem cells play a role in inducing peripheral tolerance and modulation of the immune response [5]. Proinflammatory cytokines such as IL-1β and IL-18 are leaderless secreted proteins. It has been shown that IL-1β is efficiently released from immune cells in association to MVs containing the cytokine. Shedding of MV requires stimulation of membrane receptors for the extracellular nucleotides [6]. IL-18, previously named IFN-γ-inducing factor for its ability to stimulate IFN-γ production in T lymphocytes and natural killer cells, is one of the main cytokines contributing to the pathogenesis of autoimmune and inflammatory diseases [7]. Besides lymphocytes, IL-18 is secreted by a variety of cell types including epithelial cells, keratinocytes, synovial fibroblasts, monocytes, macrophages, and DCs [8,9], thus inducing the synthesis of other proinflammatory cytokines (IFN-γ, IL-1β...

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Section: Introductionmentioning

confidence: 99%

“…Microvesicles (MVs) are small vesicles derived from the plasma membrane of eukaryotic cells [1,2]. MVs are gaining momen-observations have shown that MVs shed by mesenchymal stem cells play a role in inducing peripheral tolerance and modulation of the immune response [5].…”

Section: Introductionmentioning

confidence: 99%

IL‐18 associates to microvesicles shed from human macrophages by a LPS/TLR‐4 independent mechanism in response to P2X receptor stimulation

et al. 2012

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“…Elevated EV levels in the blood from cancer patients compared to healthy individuals has been demonstrated by various investigators [49 -51]. EV release has also been shown to aid tumour spread and survival as EVs transport various pathological growth factor receptors, soluble proteins and micro RNAs [5,6,8]. Interestingly, EV shedding from cancer cells also aids increased active drug efflux and thus contributes to their resistance to chemotherapeutic agents [11,52].…”

Section: Evs In Cancermentioning

confidence: 99%

“…This increase in cytosolic calcium results in cytoskeletal reorganisation, loss of membrane asymmetry, membrane blebbing and subsequent EV formation and release. The cytoskeletal rearrangement is known to be facilitated by the activation of various enzymes, including calpain, gelsolin, scramblase and protein kinase and the simultaneous inhibition of translocase and phosphatases [8]. In addition, recent discoveries on peptidylarginine deiminase (PAD)-mediated deimination of cytoskeletal proteins and histones have elucidated a novel crucial pathway in the facilitation of EV release [7].…”

Section: Introductionmentioning

confidence: 99%

“…As EVs are present in body fluids including blood, urine and cerebrospinal fluid, the identity of circulating EVs may serve as reliable biomarkers of pathophysiological processes [1,2,8,9]. EVs are emerging as novel therapeutic targets in treatment of disease as they have been shown to actively contribute to the progression of numerous pathologies including autoimmune diseases [8,10], cancers [7,11,12] and more recently neurodegenerative diseases [9,[13][14][15][16][17][18][19]. Novel discoveries of mechanistic pathways involved, provide potential for the development of new diagnostic assays directed at identifying early stages of disease and response to therapy [1,2].…”

Section: Introductionmentioning

confidence: 99%

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Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Lange¹,

Kholia²,

Kosgodage³

et al. 2017

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Extracellular vesicle (EV) release, which occurs in most eukaryotic cells, has recently been associated with peptidylarginine deiminase (PAD)-driven protein deimination. Evidence points to the involvement of deiminated cytoskeletal proteins and changes in histone deimination. Both PADs and EVs are associated with various pathologies including cancers, autoimmune and neurodegenerative diseases. The elevated PAD expression observed in cancers may contribute to increase in EV shedding observed from cancer cells, contributing to cancer progression. Similarly, elevated PAD expression observed in neurodegenerative diseases may cause increased EV shedding and spread of neurodegenerative EV cargo, contributing to disease progression and pathologies. Pharmacological inhibition of PAD-mediated deimination using pan-PAD inhibitor Cl-amidine, reduced cellular EV release in prostate cancer cells, rendering them significantly more susceptible to chemotherapeutic drugs. Studies on models of central nervous system damage have demonstrated critical functional roles for PADs and neuroprotective effects using PAD inhibitors in vivo, while human neurodegenerative iPSC in vitro models showed evidence of increased protein deimination. Besides using refined PAD inhibitors to selectively manipulate EV biogenesis for novel combination therapies in cancer treatment, we also speculate how EV biogenesis could be targeted via the newly identified PAD-pathway to ameliorate neurodegenerative disease progression.

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The emerging role of exosome and microvesicle- (EMV-) based cancer therapeutics and immunotherapy

et al. 2017

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There is an urgent need to develop new combination therapies beyond existing surgery, radio- and chemo-therapy, perhaps initially combining chemotherapy with the targeting specificities of immunotherapy. For this, strategies to limit inflammation and immunosuppression and evasion in the tumour microenvironment are also needed. To devise effective new immunotherapies we must first understand tumour immunology, including the roles of T cells, macrophages, myeloid suppressor cells and of exosomes and microvesicles (EMVs) in promoting angiogenesis, tumour growth, drug resistance and metastasis. One promising cancer immunotherapy discussed uses cationic liposomes carrying tumour RNA (RNA-lipoplexes) to provoke a strong anti-viral-like (cytotoxic CD8 ) anti-tumour immune response. Mesenchymal stem cell-derived EMVs, with their capacity to migrate towards inflammatory areas including solid tumours, have also been used. As tumour EMVs clearly exacerbate the tumour microenvironment, another therapy option could involve EMV removal. Affinity-based methods to deplete EMVs, including an immunodepletion, antibody-based affinity substrate, are therefore considered. Finally EMV and exosome-mimetic nanovesicles (NVs) delivery of siRNA or chemotherapeutic drugs that target tumours using peptide ligands for cognate receptors on the tumour cells are discussed. We also touch upon the reversal of drug efflux in EMVs from cancer cells which can sensitize cells to chemotherapy. The use of immunotherapy in combination with the advent of EMVs provides potent therapies to various cancers.

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Microvesicles in Health and Disease

Cited by 60 publications

References 141 publications

IL‐18 associates to microvesicles shed from human macrophages by a LPS/TLR‐4 independent mechanism in response to P2X receptor stimulation

IL‐18 associates to microvesicles shed from human macrophages by a LPS/TLR‐4 independent mechanism in response to P2X receptor stimulation

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

The emerging role of exosome and microvesicle- (EMV-) based cancer therapeutics and immunotherapy

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