New developments in mast cell biology

Kalesnikoff, Janet; Galli, Stephen J.

doi:10.1038/ni.f.216

Cited by 647 publications

(566 citation statements)

References 116 publications

(154 reference statements)

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“…We used tumor mast cells (rat basophilic leukemia cells, RBL‐2H3; Kalesnikoff & Galli, 2008; Wollman & Meyer, 2012) which secrete only part (~30%) of their stored inflammatory agents in response to maximal antigen stimulation (Fig 1A), consistent with the existence of inhibitory pathways that prevent the release of the remaining vesicles. Since previous studies proposed that PKCB is the main PKC isoform regulating mast cell secretion (Nechushtan et al , 2000), we confirmed that inhibition of PKCB with ruboxistaurin (Ishii et al , 1996; Tsai et al , 2014) further reduces the amount of released vesicles in a dose‐dependent manner following stimulation with antigen (Fig 1A) or simultaneous addition of the PKC activators phorbol ester and Ca 2+ ionophore (Fig EV1A).…”

Section: Resultsmentioning

confidence: 83%

“…Phosphorylation of VAMP8 at these internal residues can ensure that the secretion response to even strong PKC stimuli is terminated and that only a fraction of the stored vesicles is released. In the case of mast cells, this is important as secretion needs to be tightly regulated to prevent overreach such as anaphylactic shock (Kalesnikoff & Galli, 2008). Based on our evolutionary analysis, the universal conservation of internal serine and threonine residues inside SNARE complexes suggests that suppression by VAMP phosphorylation is a general mechanism by which cells can reduce non‐synaptic vesicle fusion and thereby prevent the complete release of all secretory vesicles.…”

Section: Discussionmentioning

confidence: 99%

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Phosphorylation of residues inside the SNARE complex suppresses secretory vesicle fusion

et al. 2016

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Membrane fusion is essential for eukaryotic life, requiring SNARE proteins to zipper up in an α‐helical bundle to pull two membranes together. Here, we show that vesicle fusion can be suppressed by phosphorylation of core conserved residues inside the SNARE domain. We took a proteomics approach using a PKCB knockout mast cell model and found that the key mast cell secretory protein VAMP8 becomes phosphorylated by PKC at multiple residues in the SNARE domain. Our data suggest that VAMP8 phosphorylation reduces vesicle fusion in vitro and suppresses secretion in living cells, allowing vesicles to dock but preventing fusion with the plasma membrane. Markedly, we show that the phosphorylation motif is absent in all eukaryotic neuronal VAMPs, but present in all other VAMPs. Thus, phosphorylation of SNARE domains is a general mechanism to restrict how much cells secrete, opening the door for new therapeutic strategies for suppression of secretion.

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Section: Resultsmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Phosphorylation of residues inside the SNARE complex suppresses secretory vesicle fusion

et al. 2016

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“…7,8 Upon activation, they release a plethora of pro-tumorigenic mediators, such as IL-8, VEGF, matrix metalloproteinases and proteases. 7,9 Angiogenesis factors (e.g., IL-8) and growth factors (e.g., VEGF) facilitate tumor growth and angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models

Blokhuis

Derks

et al. 2018

OncoImmunology

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Chronic inflammation drives the development of colorectal cancer (CRC), where tumor-infiltrating immune cells interact with cancer cells in a dynamic crosstalk. Mast cells (MC), one of earliest recruited immune cells, accumulate in CRC tissues and their density is correlated with cancer progression. However, the exact contribution of MC in CRC and their interaction with colon cancer cells is poorly understood. Here, we investigated the impact of primary human MC and their mediators on colon cancer growth using 2D and 3D coculture models. Primary human MC were generated from peripheral CD34+ stem cells. Transwell chambers were used to analyze MC chemotaxis to colon cancer. Colon cancer cells HT29 and Caco2 differentially recruited MC by releasing CCL15 or SCF, respectively. Using BrdU proliferation assays, we demonstrated that MC can directly support colon cancer proliferation and this effect was mediated by their cellular crosstalk. 3D coculture models with cancer spheroids further confirmed the pro-tumor effect of MC on colon cancer growth, where direct cell-cell contact is dispensable and increased production of multiple soluble mediators was detected. Moreover, TLR2 stimulation of MC promoted stronger growth of colon cancer spheroids. By examining the transcriptome profile of colon cancer-cocultured MC versus control MC, we identified several MC marker genes, which were deregulated in expression. Our study provides an advanced in vitro model to investigate the role of human MC in cancer. Our data support the detrimental role of MC in CRC development and provide a molecular insight into the cellular crosstalk between MC and colon cancer cells.

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“…Mast cells have been shown to produce a number of cytokines upon activation, for example, IL‐6, IL‐13, and TNF‐α 1. To determine whether a serglycin:serine protease axis also could regulate the levels of cytokines endogenously produced by mast cells, mast cells were stimulated with either IgE receptor cross‐linking or calcium ionophore, followed by measurements of released IL‐6 and IL‐17A.…”

Section: Resultsmentioning

confidence: 99%

“…Mast cells mainly exert their functions through the release of a wide variety of granule‐stored and de novo‐synthesized mediators 1, 2. One of the major granule components is serglycin proteoglycan, which is composed of a core protein to which highly sulfated heparin chains are attached.…”

Section: Introductionmentioning

confidence: 99%

IL‐6 and IL‐17A degradation by mast cells is mediated by a serglycin:serine protease axis

Waern

Karlsson

Pejler³

et al. 2015

Immunity, Inflammation and Disease

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Mast cells contain large amounts of fully active proteases that are stored in complex with serglycin proteoglycan in their secretory granules. Upon degranulation, such serglycin:protease complexes are released to the extracellular space and can potentially have an impact on the local inflammatory reaction, either through direct effects of serglycin proteoglycan or through effects mediated by its bound proteases. The objective of this study was to address this scenario by investigating the possibility that serglycin‐associated proteases can regulate levels of pro‐inflammatory cytokines. Indeed, we show here that activated cultured peritoneal mast cells from wild type mice efficiently reduced the levels of exogenously administered IL‐6 and IL‐17A, whereas serglycin‐deficient mast cells lacked this ability. Furthermore, our data suggest that the reduction of IL‐6 and IL‐17A concentrations is due to proteolytic degradation mediated by serglycin‐dependent serine proteases. Moreover, we show that activated mast cells have the capacity to release IL‐6 and that the levels of this cytokine in supernatants were markedly higher in cultures of serglycin‐deficient versus serglycin‐sufficient mast cells, suggesting that serglycin‐dependent serine proteases also participate in the regulation of endogenously produced IL‐6. In summary, although the general consensus is that mast cells have a pathogenic impact on inflammatory settings, this study identifies a role for a mast cell‐derived serglycin:serine protease axis in down‐regulating levels of major inflammatory cytokines. These findings support the notion that mast cells could have a dual role in inflammatory settings, by both being able to secrete pathogenic compounds and being able to regulate their levels after release.

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New developments in mast cell biology

Cited by 647 publications

References 116 publications

Phosphorylation of residues inside the SNARE complex suppresses secretory vesicle fusion

Phosphorylation of residues inside the SNARE complex suppresses secretory vesicle fusion

Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models

IL‐6 and IL‐17A degradation by mast cells is mediated by a serglycin:serine protease axis

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