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

被引:42
|
作者
Wang, Zhao [1 ,2 ]
Guhl, Sven [1 ,2 ]
Franke, Kristin [1 ,2 ]
Artuc, Metin [1 ,2 ]
Zuberbier, Torsten [1 ,2 ]
Babina, Magda [1 ,2 ]
机构
[1] Charite Univ Med Berlin, Dept Dermatol Venerol & Allergy, Charitepl 1, D-10117 Berlin, Germany
[2] Humboldt Univ, Freie Univ Berlin, Charitepl 1, D-10117 Berlin, Germany
关键词
mast cells; skin; IL-33; pseudo-allergy; neurogenic mast cell activation; neuropeptides; MRGPRX2; degranulation; JNK; p38; HOST-DEFENSE PEPTIDE; CELL ACTIVATION; PROTEIN-KINASE; P38; MAPK; INTERLEUKIN-33; IL-33; CHYMASE; ROLES; INFLAMMATION; CYTOKINES; RELEASE;
D O I
10.3390/cells8040341
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Clinically relevant exocytosis of mast cell (MC) mediators can be triggered by high-affinity IgE receptor (Fc epsilon RI)-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 Fc epsilon RI-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((R))-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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页数:17
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