Suppression of IgE-Independent Degranulation of Murine Connective Tissue-Type Mast Cells by Dexamethasone

Yamada, Keiko; Sato, Hitomi; Sakamaki, Kazuma; Kamada, Mayumi; Okuno, Yasushi; Fukuishi, Nobuyuki; Furuta, Kazuyuki; Tanaka, Satoshi

doi:10.3390/cells8020112

Cited by 13 publications

(14 citation statements)

References 40 publications

(45 reference statements)

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“…The combined findings from our previous report [24] and this study indicate that long-term IL-33 may yield effects reminiscent of long-term exposure to glucocorticoids, as reported recently by Yamada and colleagues for murine CTMC [57]. In fact, we found reduced chymase mRNA, coupled with increased histidine decarboxylase/histamine abundance [24], and a nearly abrogated MRGPRX2 pathway in this report, a triad of manifestations likewise detected for dexamethasone [57]. IL-33 and glucocorticoids may thus employ overlapping strategies to cause this phenotypic switch in MCs.…”

Section: Discussionsupporting

confidence: 83%

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IL-33 and MRGPRX2-Triggered Activation of Human Skin Mast Cells—Elimination of Receptor Expression on Chronic Exposure, but Reinforced Degranulation on Acute Priming

Wang

Guhl

Franke

et al. 2019

Cells

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Clinically relevant exocytosis of mast cell (MC) mediators can be triggered by high-affinity IgE receptor (FcεRI)-aggregation (allergic route) or by the so-called pseudo-allergic pathway elicited via MAS-related G protein-coupled receptor-X2 (MRGPRX2). The latter is activated by drugs and endogenous neuropeptides. We recently reported that FcεRI-triggered degranulation is attenuated when human skin mast cells are chronically exposed to IL-33. Here, we were interested in the regulation of the MRGPRX2-route. Chronic exposure of skin MCs to IL-33 basically eliminated the pseudo-allergic/neurogenic route as a result of massive MRGPRX2 reduction. This downregulation seemed to partially require c-Jun N-terminal Kinase (JNK), but not p38, the two kinases activated by IL-33 in skin MCs. Surprisingly, however, JNK had a positive effect on MRGPRX2 expression in the absence of IL-33. This was evidenced by Accell®-mediated JNK knockdown and JNK inhibition. In stark contrast to the dampening effect upon prolonged exposure, IL-33 was able to prime for increased degranulation by MRGPRX2 ligands when administered directly before stimulation. This supportive effect depended on p38, but not on JNK activity. Our data reinforce the concept that exposure length dictates whether IL-33 will enhance or attenuate secretion. IL-33 is, thus, the first factor to acutely enhance MRGPRX2-triggered degranulation. Finally, we reveal that p38, rarely associated with MC degranulation, can positively affect exocytosis in a context-dependent manner.

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Section: Discussionsupporting

confidence: 83%

“…Conversely, an acute burst of IL-33 supports secretion, likely to foster MC-dependent defense strategies. An anti-inflammatory character on prolonged exposure to IL-33 is also highlighted by its resemblance with MC responses to sustained glucocorticoids [57].…”

Section: Discussionmentioning

confidence: 99%

IL-33 and MRGPRX2-Triggered Activation of Human Skin Mast Cells—Elimination of Receptor Expression on Chronic Exposure, but Reinforced Degranulation on Acute Priming

Wang

Guhl

Franke

et al. 2019

Cells

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“…Because BMMCs are highly capable for further differentiation into mature mast cells, local reconstitution of BMMCs in recently developed mast-cell-deficient mice has been used as one of the best suitable approaches to clarify the functions of tissue mast cells [17]. We previously established a modified coculture method of BMMCs using murine fibroblastic cell line, Swiss 3T3, which shared many characteristics with murine cutaneous mast cells [18,19]. We tried to develop here a novel culture model, in which BMMCs were further cultured in the presence of IL-9 and SCF.…”

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confidence: 99%

Establishment and Characterization of a Murine Mucosal Mast Cell Culture Model

Kakinoki

Kameo

Shoko

et al. 2019

IJMS

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Accumulating evidence suggests that mast cells play critical roles in disruption and maintenance of intestinal homeostasis, although it remains unknown how they affect the local microenvironment. Interleukin-9 (IL-9) was found to play critical roles in intestinal mast cell accumulation induced in various pathological conditions, such as parasite infection and oral allergen-induced anaphylaxis. Newly recruited intestinal mast cells trigger inflammatory responses and damage epithelial integrity through release of a wide variety of mediators including mast cell proteases. We established a novel culture model (IL-9-modified mast cells, MCs/IL-9), in which murine IL-3-dependent bone-marrow-derived cultured mast cells (BMMCs) were further cultured in the presence of stem cell factor and IL-9. In MCs/IL-9, drastic upregulation of Mcpt1 and Mcpt2 was found. Although histamine storage and tryptase activity were significantly downregulated in the presence of SCF and IL-9, this was entirely reversed when mast cells were cocultured with a murine fibroblastic cell line, Swiss 3T3. MCs/IL-9 underwent degranulation upon IgE-mediated antigen stimulation, which was found to less sensitive to lower concentrations of IgE in comparison with BMMCs. This model might be useful for investigation of the spatiotemporal changes of newly recruited intestinal mast cells.Int. J. Mol. Sci. 2020, 21, 236 2 of 13 the intestinal nematodes and local mastocytosis in epithelial layer of the gut, trachea and kidney [8][9][10]. The number of intestinal mast cells were unchanged in the gene-targeted mice lacking IL-9 or IL-9 receptor-α chain, whereas oral-antigen-induced accumulation of intestinal mast cells was impaired in these mice [11,12]. These findings indicate that IL-9 should trigger intestinal mastocytosis upon parasite infection and newly recruited mast cells should make a significant contribution towards worm expulsion. IL-9 was found to enhance stem cell factor (SCF)-mediated proliferation of murine bone-marrow-derived cultured mast cells, although IL-9 alone could not support mast cell growth and survival [13]. It remains largely unknown how transdifferentiation of intestinal mast cells should occur under the influence of IL-9 and SCF.IL-3-dependent bone-marrow-derived cultured mast cells (BMMCs) have been investigated as a useful model of murine immature mast cells. BMMCs were initially regarded as a model of mucosal mast cells, because they stored chondroitin sulphate E, rather than heparin, in their granules and had lower amounts of histamine, both being characteristic of persistent mucosal mast cells [14]. However, accumulating evidence has suggested that there are many differences among BMMCs, resident mucosal mast cells and recruited mast cells upon parasite infection. IL-3 was found to play critical roles in parasite expulsion and intestinal mastocytosis [15]. Murine mucosal mast cells recruited upon parasite infection were found to highly express a series of chymase genes, such as Mcpt1 [16], although little or no expression of the...

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“…The purpose of this study was to determine if noncytotoxic synthetic smHDPMs that display antifungal and antibacterial activity promote human MC degranulation via MRGPRX2. Although Mrgprb2 was originally identified as the mouse ortholog of human MRGPRX2 in CTMCs [8], a recent study demonstrated that Mrgprb1, Mrgprb10, and Mrgprc11 are also expressed in MCs [33]. Another goal of this study was to determine which of the mouse Mas-related GPCRs contribute to degranulation in response to smHDPMs.…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Host-Defense Peptide Mimetic Antibacterial and Antifungal Agents Activate Human and Mouse Mast Cells via Mas-Related GPCRs

Alkanfari

Freeman

Roy

et al. 2019

Cells

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Host-defense peptides (HDPs) have an important therapeutic potential against microbial infections but their metabolic instability and cellular cytotoxicity have limited their utility. To overcome these limitations, we utilized five small-molecule, nonpeptide HDP mimetics (smHDPMs) and tested their effects on cytotoxicity, antimicrobial activity, and mast cell (MC) degranulation. None of the smHDPMs displayed cytotoxicity against mouse 3T3 fibroblasts or human transformed liver HepG2 cells. However, one compound had both antifungal and antibacterial activity. Surprisingly, all five compounds induced degranulation in a human MC line, LAD2, and this response was substantially reduced in Mas-related G protein-coupled receptor (GPCR)-X2 (MRGPRX2)-silenced cells. Furthermore, all five compounds induced degranulation in RBL-2H3 cells expressing MRGPRX2 but this response was abolished in cells expressing naturally occurring loss-of-function missense variants G165E (rs141744602) and D184H (rs372988289). Mrgprb2 is the likely mouse ortholog of human MRGPRX2, which is expressed in connective tissue MCs (CTMCs) such as cutaneous and peritoneal MCs (PMCs). All five smHDPMs induced degranulation in wild-type PMCs but not in cells derived from Mrgprb2-/- mice. These findings suggest that smHDPMs could serve as novel targets for the treatment of drug-resistant fungal and bacterial infections because of their ability to harness CTMCs’ host defense functions.

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Suppression of IgE-Independent Degranulation of Murine Connective Tissue-Type Mast Cells by Dexamethasone

Cited by 13 publications

References 40 publications

IL-33 and MRGPRX2-Triggered Activation of Human Skin Mast Cells—Elimination of Receptor Expression on Chronic Exposure, but Reinforced Degranulation on Acute Priming

IL-33 and MRGPRX2-Triggered Activation of Human Skin Mast Cells—Elimination of Receptor Expression on Chronic Exposure, but Reinforced Degranulation on Acute Priming

Establishment and Characterization of a Murine Mucosal Mast Cell Culture Model

Small-Molecule Host-Defense Peptide Mimetic Antibacterial and Antifungal Agents Activate Human and Mouse Mast Cells via Mas-Related GPCRs

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