Different activation signals induce distinct mast cell degranulation strategies
Different activation signals induce distinct mast cell degranulation strategies
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DOI：
10.1172/jci85538
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发表时间：
2016-10-01
影响因子：
15.9
通讯作者：
Galli, Stephen J.
中科院分区：
文献类型：
--
作者：
Gaudenzio, Nicolas;Sibilano, Riccardo;Galli, Stephen J.
肥大细胞（MCs）通过分泌含有多种介质的胞质颗粒影响炎症期间的细胞间通讯。在这里，我们已经证明了MCs将不同的激活刺激解码为空间和时间上不同的颗粒分泌模式。某些信号，包括P物质、补体过敏毒素C3a和C5a以及内皮素1，诱导人MCs迅速分泌小而相对球形的颗粒结构，这种模式与单个颗粒的分泌一致。相反，用抗ige激活MCs增加了信号传导和分泌之间的时间间隔，这与细胞内钙的持续升高和形成更大、形状更不均匀的颗粒结构有关，这些颗粒结构经历了长时间的外化。在ige依赖刺激过程中，ikk - β的药理抑制显著降低了信号和分泌之间的时间间隔，抑制了SNAP23/STX4复合物的形成，并将脱粒模式切换为类似于p物质诱导的脱粒模式。体内的ige依赖和p物质依赖激活也诱导了小鼠MC脱粒的不同模式，这些模式与不同的局部和全身病理生理反应相关。这些发现表明，在不同的激活刺激下，MCs的细胞质颗粒分泌可以表现出不同的动态和特征，这些特征与不同的mc依赖性炎症模式相关。
Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-beta during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P-dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation.