Microglial microvesicle secretion and intercellular signaling

Turola, Elena; Furlan, Roberto; Bianco, Fabio; Matteoli, Michela; Verderio, Claudia

doi:10.3389/fphys.2012.00149

Cited by 149 publications

(160 citation statements)

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“…Macrophages were cultured in RPMI-1640 medium (Life Technologies, Gaithersburg, MD, USA) supplemented with 5% heat-inactivated human AB serum (Sigma, Milan, Italy). Standard saline solution contained: 300 mM sucrose, 1 mM K 2 …”

Section: Cells and Solutionsmentioning

confidence: 99%

“…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%

“…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.…”

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 potentiates the immune response against viruses but has also been linked to the pathogenesis of atherosclerosis, active psoriasis, systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, and graftversus-host disease [44]. It has recently been reported that besides the soluble form, IL-18 is expressed as a membrane-bound protein in human blood CD16 − and CD16 + monocytes differentiating to macrophages by M-CSF stimulation [45].Human macrophages were chosen as a cell model for this study since they produce IL-18 and express several P2 receptor subtypes, particularly P2X7 that has been previously shown to trigger MVs release from other cell types [2,24]. Here we show that stimulation of human macrophages with the pan P2 agonist ATP or the P2X7 agonist BzATP induced shedding of MVs within minutes.…”

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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: Cells and Solutionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

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

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Functional deficiency in endogenous interleukin‐1 receptor antagonist in patients with febrile infection‐related epilepsy syndrome

Clarkson

LaFrance‐Corey

Kahoud

et al. 2019

Annals of Neurology

125

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Objective We recently reported successful treatment of a child with febrile infection‐related epilepsy syndrome (FIRES), a subtype of new onset refractory status epilepticus, with the recombinant interleukin‐1 (IL1) receptor antagonist (IL1RA) anakinra. On this basis, we tested whether endogenous IL1RA production or function is deficient in FIRES patients. Methods Levels of IL1β and IL1RA were measured in serum and cerebrospinal fluid (CSF). The inhibitory activity of endogenous IL1RA was assessed using a cell‐based reporter assay. IL1RN gene variants were identified by sequencing. Expression levels for the secreted and intracellular isoforms of IL1RA were measured in patient and control cells by real‐time polymerase chain reaction. Results Levels of endogenous IL1RA and IL1β were elevated in the serum and CSF of patients with FIRES (n = 7) relative to healthy controls (n = 10). Serum from FIRES patients drove IL1R signaling activity and potentiated IL1R signaling in response to exogenous IL1β in a cell‐based reporter assay. Functional assessment of endogenous IL1RA activity in 3 FIRES patients revealed attenuated inhibition of IL1R signaling. Sequencing of IL1RN in our index patient revealed multiple variants. This was accompanied by reduced expression of intracellular but not secreted isoforms of IL1RA in the patient's peripheral blood mononuclear cells. Interpretation Our findings suggest that FIRES is associated with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity. These observations may provide insight into disease pathogenesis for FIRES and other inflammatory seizure disorders and may provide a valuable biomarker for therapeutic decision‐making. Ann Neurol 2019;85:526–537

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Microglial modulation of neuronal activity in the healthy brain

York

Bernier

MacVicar

2017

Developmental Neurobiology

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Investigations on the role of microglia in the brain have traditionally been focused on their contributions to disease states. However, recent observations have now convincingly shown that microglia in the healthy brain are not passive bystanders, but instead play a critical role in both central nervous system development and homeostasis of synaptic circuits in the adult. Here, we review the various mechanisms by which microglia impact neuronal communication in the healthy adult brain, both by sensing nearby synaptic responses and by actively modulating neuronal function. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 593-603, 2018.

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Microglial microvesicle secretion and intercellular signaling

Cited by 149 publications

References 121 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

Functional deficiency in endogenous interleukin‐1 receptor antagonist in patients with febrile infection‐related epilepsy syndrome

Microglial modulation of neuronal activity in the healthy brain

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