Serglycin Proteoglycan Promotes Apoptotic versus Necrotic Cell Death in Mast Cells

Melo, Fabio Rabelo; Grujić, Mirjana; Spirkoski, Jane; Calounova, Gabriela; Pejler, Gunnar

doi:10.1074/jbc.m112.344796

Cited by 19 publications

(15 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The latter is in agreement with previous findings showing that a serglycin‐tryptase axis is an important regulator of apoptotic versus necrotic cell death in response to various other types of cell stress (Melo et al. , ; Spirkoski et al. ).…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies have suggested that serglycin, a proteoglycan that is abundant in mast cell granules, and tryptase, the latter a serine protease that is stored in complex with serglycin, can have an impact on the mechanism of cell death in mast cells (Melo et al. ). To assess the role of these compounds in mefloquine‐induced cell death, we incubated WT, serglycin −/− and tryptase (mMCP‐6) −/− mast cells with mefloquine followed by Annexin V/PI staining.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Mefloquine, an anti‐malaria agent, causes reactive oxygen species‐dependent cell death in mast cells via a secretory granule‐mediated pathway

Paivandy

Calounova

Zarnegar

et al. 2014

Pharmacology Res & Perspec

Self Cite

View full text Add to dashboard Cite

Mast cells are known to have a detrimental impact on a variety of pathological conditions. There is therefore an urgent need of developing strategies that limit their harmful effects. The aim of this study was to accomplish this by developing a means of inducing mast cell apoptosis. The strategy was to identify novel compounds that induce mast cell apoptosis by permeabilization of their secretory lysosomes (granules). As a candidate, we assessed mefloquine, an anti-malarial drug that has been proposed to have lysosome-permeabilizing activity. Mefloquine was added to mast cells and administered in vivo, followed by assessment of the extent and mechanisms of mast cell death. Mefloquine was cytotoxic to murine and human mast cells. Mefloquine induced apoptotic cell death of wild-type mast cells whereas cells lacking the granule compounds serglycin proteoglycan or tryptase were shown to undergo necrotic cell death, the latter finding indicating a role of the mast cell granules in mefloquine-induced cell death. In support of this, mefloquine was shown to cause compromised granule integrity and to induce leakage of granule components into the cytosol. Mefloquine-induced cell death was refractory to caspase inhibitors but was completely abrogated by reactive oxygen species inhibition. These findings identify mefloquine as a novel anti-mast cell agent, which induces mast cell death through a granule-mediated pathway. Mefloquine may thus become useful in therapy aiming at limiting harmful effects of mast cells.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Mefloquine, an anti‐malaria agent, causes reactive oxygen species‐dependent cell death in mast cells via a secretory granule‐mediated pathway

Paivandy

Calounova

Zarnegar

et al. 2014

Pharmacology Res & Perspec

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mechanistically, these agents induce permeabilization of mast‐cell granule membranes, which results in the release of granule compounds into cytosol and the subsequent triggering of reactive oxygen species and tryptase‐dependent apoptosis (Fig. ) …”

Section: Discussionmentioning

confidence: 99%

Siramesine causes preferential apoptosis of mast cells in skin biopsies from psoriatic lesions

et al. 2017

View full text Add to dashboard Cite

SummaryBackground Skin mast cells are implicated as detrimental effector cells in various inflammatory skin diseases such as contact eczema, atopic dermatitis and psoriasis. Selective reduction of cutaneous mast cells, e.g. by inducing targeted apoptosis, might prove a rational and efficient therapeutic strategy in dermatoses negatively influenced by mast cells. Objectives The objective of the present study was to evaluate whether a lysosomotropic agent such as siramesine can cause apoptosis of mast cells present in psoriatic lesions. Materials and methods Punch biopsies were obtained from lesional and uninvolved skin in 25 patients with chronic plaque psoriasis. After incubation with siramesine, the number of tryptase-positive mast cells and their expression of interleukin (IL)-6 and IL-17 was analysed. Skin biopsies were digested to allow flow cytometric analysis of the drug's effect on cutaneous fibroblasts and keratinocytes. Results Siramesine caused a profound reduction in the total number of mast cells in both lesional and uninvolved psoriatic skin biopsies without affecting the gross morphology of the tissue. The drug reduced the density of IL-6-and IL-17-positive mast cells, and showed antiproliferative effects on epidermal keratinocytes but had no apparent cytotoxic effect on keratinocytes or dermal fibroblasts. Conclusions Considering the pathophysiology of psoriasis, the effects of siramesine on cutaneous mast cells may prove favourable from the therapeutic aspect. The results encourage further studies to assess the usefulness of siramesine and other lysosomotropic agents in the treatment of cutaneous mastocytoses and inflammatory skin diseases aggravated by dermal mast cells.

show abstract

“…However, we have recently shown that secretory granules and their contained serglycin-bound proteases in addition can influence cell death. When assessing the mechanism of cell death in MCs, we found that although wild type (WT) MCs predominantly die by apoptosis in response to various cytotoxic agents, cells lacking serglycin predominantly undergo necrotic cell death (9). This could potentially have a large impact on MC-mediated events, considering that apoptosis occurs with minimal damage to the surrounding milieu, whereas necrotic cell death is characterized by extensive leakage of pro-inflammatory alarmins from the interior of necrotic cells to the cell surroundings (10 -12).…”

Section: Mast Cells (Mcs)mentioning

confidence: 99%

“…Moreover, we found that the apoptosis-promoting effect of serglycin was attributed to tryptase, i.e. one of the proteases that are complex-bound to serglycin and dependent on serglycin for storage within granules (9). However, the mechanism by which the serglycin-tryptase axis regulates cell death is not known, one essential aspect being to identify the downstream intracellular targets(s) for the serglycin-tryptase axis.…”

Section: Mast Cells (Mcs)mentioning

confidence: 99%

Proteolytic Histone Modification by Mast Cell Tryptase, a Serglycin Proteoglycan-dependent Secretory Granule Protease

Melo

Vita

Berent-Maoz

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

Serglycin Proteoglycan Promotes Apoptotic versus Necrotic Cell Death in Mast Cells

Abstract: Background: Serglycin is a secretory granule proteoglycan with a role in intracellular storage. Results: In response to cell death-inducing agents, wild type mast cells die by apoptosis whereas serglycin Ϫ/Ϫ cells undergo

Cited by 19 publications

References 38 publications

Mefloquine, an anti‐malaria agent, causes reactive oxygen species‐dependent cell death in mast cells via a secretory granule‐mediated pathway

Mefloquine, an anti‐malaria agent, causes reactive oxygen species‐dependent cell death in mast cells via a secretory granule‐mediated pathway

Siramesine causes preferential apoptosis of mast cells in skin biopsies from psoriatic lesions

Proteolytic Histone Modification by Mast Cell Tryptase, a Serglycin Proteoglycan-dependent Secretory Granule Protease

Contact Info

Product

Resources

About