Mast cell–derived particles deliver peripheral signals to remote lymph nodes

Kunder, Christian A.; John, Ashley L. St.; Li, Guojie; Leong, Kam W.; Berwin, Brent; Staats, Herman F.; Abraham, Soman N.

doi:10.1084/jem.20090805

Cited by 157 publications

(178 citation statements)

References 45 publications

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“…It is generally accepted that mast cells can influence adaptive immunity through the release of inflammatory mediators (44). Recently, mast cell-derived particles containing TNF-a were identified and suggested to function as extracellular chaperones responsible for carrying signaling molecules from the periphery to the draining lymph nodes, where the interaction between lymphocytes and APCs occurs (45). In addition, evidence of a role for mast cells in Ag presentation was provided by Kambayashi et al (46).…”

Section: Discussionmentioning

confidence: 93%

p66Shc Is a Negative Regulator of FcεRI-Dependent Signaling in Mast Cells

Ulivieri

Fanigliulo

Masi

et al. 2011

The Journal of Immunology

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Aggregation of FcεRI on mast cells activates signaling pathways, resulting in degranulation and cytokine release. Release of mast cell-derived inflammatory mediators is tightly regulated by the interplay of positive and negative signals largely orchestrated by adapter proteins. Among these, the Shc family adapter p52Shc, which couples immunoreceptors to Ras activation, positively regulates FcεRI-dependent signaling. Conversely, p66Shc was shown to uncouple the TCR for the Ras–MAPK pathway and prime T cells to undergo apoptotic death. Loss of p66Shc in mice results in breaking of immunologic tolerance and development of lupus-like autoimmune disease, which includes alopecia among its pathological manifestations. The presence of numerous activated mast cells in alopecic skin areas suggests a role for this adapter in mast cells. In this study, we addressed the involvement of p66Shc in FcεRI-dependent mast cell activation. We showed that p66Shc is expressed in mast cells and that mast cells from p66Shc−/− mice exhibit enhanced responses following Ag stimulation of FcεRI. Furthermore, using RBL-2H3 cell transfectants, we showed that aggregation of FcεRI resulted in the recruitment of a p66Shc–SHIP1 complex to linker for activation of T cells. Collectively, our data identified p66Shc as a negative regulator of mast cell activation.

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Section: Discussionmentioning

confidence: 93%

p66Shc Is a Negative Regulator of FcεRI-Dependent Signaling in Mast Cells

Ulivieri

Fanigliulo

Masi

et al. 2011

The Journal of Immunology

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“…It has been shown that heparin matrix protects mast cell mediators from degradation and influences tryptase and chymase bioactivities 8,13 . Moreover, Abraham and co-workers showed that the exocyted granules can serve as nanoparticles for progressive delivery of serglycin proteoglycansembedded compounds such as TNF 11,12 . Conversely, an early study, based on biochemical approaches, reported that chymase and heparin are retained on the rat mast cell surface upon degranulation 10 .…”

Section: Discussionmentioning

confidence: 99%

“…During the degranulation process, granule membranes fuse with each other and with the plasma membrane leading to the release of granule content into the surrounding environment. Some mediators, such as histamine, serotonin or b-hexosaminidase, quickly diffuse from the released granules, whereas others, such as tryptase, chymase or tumour-necrosis factor (TNF), dissociate more slowly allowing granule remnants to keep their biological activity for a prolonged time 8,[10][11][12] . Granule enzymes play numerous roles in immune responses 13,14 .…”

mentioning

confidence: 99%

Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence

et al. 2015

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Mast cells are tissue-resident immune cells that play a key role in inflammation and allergy. Here we show that interaction of mast cells with antibody-targeted cells induces the polarized exocytosis of their granules resulting in a sustained exposure of effector enzymes, such as tryptase and chymase, at the cell-cell contact site. This previously unidentified mast cell effector mechanism, which we name the antibody-dependent degranulatory synapse (ADDS), is triggered by both IgE-and IgG-targeted cells. ADDSs take place within an area of cortical actin cytoskeleton clearance in the absence of microtubule organizing centre and Golgi apparatus repositioning towards the stimulating cell. Remarkably, IgG-mediated degranulatory synapses also occur upon contact with opsonized Toxoplasma gondii tachyzoites resulting in tryptase-dependent parasite death. Our results broaden current views of mast cell degranulation by revealing that human mast cells form degranulatory synapses with antibody-targeted cells and pathogens for dedicated secretion and defence.

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“…؊/؊ BMMCs display enhanced, constitutive release of microvesicles Upon activation, mast cells release, in addition to soluble mediators, small extracellular vesicles surrounded by a phospholipid bilayer, referred to as exosomes (50 -100 nm) or microvesicles (100 -1000 nm), which are generated by MVB exocytosis or plasma membrane budding/blebbing, respectively [8,9,25]. We investigated whether p66Shc Ϫ/Ϫ affects this process of mast cell secretion.…”

Section: P66shcmentioning

confidence: 99%

“…In addition, mast cells release extracellular vesicles containing several mediators, which have emerged as key regulators of intercellular communication [4]. These include exosomes, i.e., vesicles of 50 -100 nm in diameter that originate from MVBs and are released into the microenvironment following MVB fusion with the plasma membrane and larger vesicles of 100 -1000 nm in diameter, referred to as microvesicles, that shed from mast cells by plasma membrane budding/blebbing [7][8][9]. The release of membrane vesicles into the extracellular space is dependent on the functional state of cells and contributes to the dynamic composition of the tissue microenvironment [10]; however, the mechanisms implicated in their biogenesis and secretion as well as their interaction with target cells are as yet unclear.…”

Section: Introductionmentioning

confidence: 99%

p66Shc regulates vesicle-mediated secretion in mast cells by affecting F-actin dynamics

Masi

Mercati

Vannuccini

et al. 2013

Journal of Leukocyte Biology

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The extracellular vesicular compartment has emerged as a novel system of intercellular communication; however, the mechanisms involved in membrane vesicle biogenesis and secretion are as yet unclear. Among immune cells releasing membrane vesicles-mast cells that reside near tissues exposed to the environmentare master modulators of immune responses. Here, we have addressed the role of p66Shc, a novel regulator of mast cell activation and homeostasis, in the dynamic reorganization of the actin cytoskeleton that is associated with morphological changes during secretion. We show that p66Shc is recruited as a complex with the lipid phosphatase SHIP1 to the F-actin skeleton and impairs antigen-dependent cortical F-actin disassembly and membrane ruffling through the inhibition of Vav and paxillin phosphorylation. We also show that in addition to acting as a negative regulator of antigen-dependent mast cell degranulation, p66Shc limits the basal release of granule contents by inhibiting microvesicle budding from the plasma membrane and piecemeal degranulation. These findings identify p66Shc as a critical regulator of actin dynamics in mast cells, providing a basis for understanding the molecular mechanisms involved in vesicle-mediated secretion in these cells.

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Mast cell–derived particles deliver peripheral signals to remote lymph nodes

Cited by 157 publications

References 45 publications

p66Shc Is a Negative Regulator of FcεRI-Dependent Signaling in Mast Cells

p66Shc Is a Negative Regulator of FcεRI-Dependent Signaling in Mast Cells

Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence

p66Shc regulates vesicle-mediated secretion in mast cells by affecting F-actin dynamics

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