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

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 341 ◽  
Author(s):  
Zhao Wang ◽  
Sven Guhl ◽  
Kristin Franke ◽  
Metin Artuc ◽  
Torsten Zuberbier ◽  
...  

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.

Immunobiology ◽  
2021 ◽  
Vol 226 (2) ◽  
pp. 152056
Author(s):  
Sakino Fukatsu ◽  
Hikari Horinouchi ◽  
Shiho Nagata ◽  
Risa Kamei ◽  
Daichi Tanaka ◽  
...  

2012 ◽  
Vol 21 (11) ◽  
pp. 878-880 ◽  
Author(s):  
Sven Guhl ◽  
Metin Artuc ◽  
Torsten Zuberbier ◽  
Magda Babina

2018 ◽  
Author(s):  
Elin Rönnberg ◽  
Avan Ghaib ◽  
Carlos Ceriol ◽  
Mattias Enoksson ◽  
Michel Arock ◽  
...  

AbstractBackgroundEpithelial cytokines, including IL-33 and TSLP, have attracted interest because of their roles in chronic allergic inflammation-related conditions such as asthma. Mast cells are one of the major targets of IL-33, to which they respond by secreting cytokines. Most studies performed thus far have investigated the acute effects of IL-33 on mast cells.ObjectiveThe objective of this study is to investigate how acute versus prolonged exposure of human mast cells to IL-33 and TSLP affects mediator synthesis and IgE-mediated activation.MethodsHuman lung mast cells (HLMCs), cord blood-derived mast cells (CBMCs), and the ROSA mast cell line were used for this study. Surface receptor expression and the levels of mediators were measured after treatment with IL-33 and/or TSLP.ResultsIL-33 induced the acute release of cytokines. Prolonged exposure to IL-33 increased while TSLP reduced intracellular levels of tryptase. Acute IL-33 treatment strongly potentiated IgE-mediated activation. In contrast, four days of exposure to IL-33 decreased IgE-mediated activation, an effect that was accompanied by a reduction in FcεRI expression.Conclusion & Clinical RelevanceWe show that IL-33 plays dual roles for mast cell functions. The acute effect includes cytokine release and the potentiation of IgE-mediated degranulation, whereas prolonged exposure to IL-33 reduces IgE-mediated activation. We conclude that mast cells act quickly in response to the alarmin IL-33 to initiate an acute inflammatory response, whereas extended exposure to IL-33 during prolonged inflammation reduces IgE-mediated responses. This negative feedback effect suggests the presence of a novel IL-33 mediated regulatory pathway that modulates IgE-induced human mast cell responses.


2017 ◽  
Vol 37 (7) ◽  
Author(s):  
Xiaocui Zhang ◽  
Geneviève Lavoie ◽  
Antoine Méant ◽  
Léo Aubert ◽  
Marie Cargnello ◽  
...  

ABSTRACT The scaffolding adapter protein Gab2 (Grb2-associated binder) promotes cell proliferation, survival, and motility by engaging several signaling pathways downstream of growth factor and cytokine receptors. In particular, Gab2 plays essential roles in mast cells, as it is required for phosphoinositide 3-kinase (PI3K) activation in response to Kit and the high-affinity IgE receptor. While the positive role of Gab2 in PI3K signaling is well documented, very little is known about the mechanisms that attenuate its function. Here we show that Gab2 becomes phosphorylated on multiple proline-directed sites upon stimulation of the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. We demonstrate that ERK1 and ERK2 interact with Gab2 via a novel docking motif, which is required for subsequent Gab2 phosphorylation in response to ERK1/2 activation. We identified four ERK1/2-dependent phosphorylation sites in Gab2 that prevent the recruitment of the p85 regulatory subunit of PI3K. Using bone marrow-derived mast cells to study Gab2-dependent signaling, we found that the inhibition of ERK1/2 activity promotes Akt signaling in response to Kit and the high-affinity IgE receptor. Together, our results indicate that ERK1/2 participates in a negative-feedback loop that attenuates PI3K/Akt signaling in response to various agonists.


Allergy ◽  
2006 ◽  
Vol 61 (3) ◽  
pp. 303-310 ◽  
Author(s):  
B. M. Jensen ◽  
K. Assing ◽  
L. Hummelshoj ◽  
C. Glue ◽  
P. S. Skov ◽  
...  

2009 ◽  
Vol 184 (1) ◽  
pp. 84-93 ◽  
Author(s):  
Michael Poderycki ◽  
Yoshiaki Tomimori ◽  
Tomoaki Ando ◽  
Wenbin Xiao ◽  
Mari Maeda-Yamamoto ◽  
...  

2001 ◽  
Vol 107 (1) ◽  
pp. 114-122 ◽  
Author(s):  
Philippe Gosset ◽  
Catherine Lamblin-Degros ◽  
Isabelle Tillie-Leblond ◽  
Anne-Sophie Charbonnier ◽  
Michel Joseph ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document