Interleukin-33 Amplifies Human Mast Cell Activities Induced by Complement Anaphylatoxins.
Interleukin-33 Amplifies Human Mast Cell Activities Induced by Complement Anaphylatoxins.
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DOI：
10.3389/fimmu.2020.615236
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发表时间：
2020
影响因子：
7.3
通讯作者：
Bulfone-Paus S
中科院分区：
文献类型：
--
作者：
West PW;Bahri R;Garcia-Rodriguez KM;Sweetland G;Wileman G;Shah R;Montero A;Rapley L;Bulfone-Paus S
异常肥大细胞反应和补体激活都有助于过敏性疾病。由于肥大细胞对C3a和C5a高度敏感，而白细胞介素-33 （IL-33）是一种有效的肥大细胞激活剂，我们假设IL-33对肥大细胞对补体过敏毒素的反应起关键调节作用。我们试图了解C3a和C5a对人原代肥大细胞的激活是否存在差异，并探究IL-33是否调节C3a/C5a诱导的肥大细胞活性。原代人肥大细胞由外周血前体生成或从健康人肺组织分离，并评估肥大细胞补体受体表达、脱颗粒、介质释放、磷酸化模式和钙通量。不同来源的人肥大细胞表达C3aR1的组成性水平高于C5aR1，并且这两种受体都被过敏毒素下调。虽然C3a是一种有效的肥大细胞脱颗粒诱导剂，但C5a是一种较弱的促分泌剂，其延迟作用更大。重要的是，IL-33可以增强人肥大细胞对C3a和C5a的反应性（脱颗粒、细胞因子和趋化因子释放），而不依赖于C3a或C5a受体表达或Ca2+内流水平的变化。相反，这反映了细胞内信号传导的差异动力学，如ERK1/2磷酸化。由于原代人肥大细胞对过敏毒素刺激的反应不同，而IL-33是肥大细胞对补体过敏毒素反应的关键调节因子，这可能会加重Th2免疫反应。这种新发现的交叉调节可能对控制补体和肥大细胞依赖性Th2反应的加剧很重要，因此为靶向抗il33治疗过敏性疾病提供了额外的理论依据。
Both, aberrant mast cell responses and complement activation contribute to allergic diseases. Since mast cells are highly responsive to C3a and C5a, while Interleukin-33 (IL-33) is a potent mast cell activator, we hypothesized that IL-33 critically regulates mast cell responses to complement anaphylatoxins. We sought to understand whether C3a and C5a differentially activate primary human mast cells, and probe whether IL-33 regulates C3a/C5a-induced mast cell activities. Primary human mast cells were generated from peripheral blood precursors or isolated from healthy human lung tissue, and mast cell complement receptor expression, degranulation, mediator release, phosphorylation patterns, and calcium flux were assessed. Human mast cells of distinct origin express constitutively higher levels of C3aR1 than C5aR1, and both receptors are downregulated by anaphylatoxins. While C3a is a potent mast cell degranulation inducer, C5a is a weaker secretagogue with more delayed effects. Importantly, IL-33 potently enhances the human mast cell reactivity to C3a and C5a (degranulation, cytokine and chemokine release), independent of changes in C3a or C5a receptor expression or the level of Ca2+ influx. Instead, this reflects differential dynamics of intracellular signaling such as ERK1/2 phosphorylation. Since primary human mast cells respond differentially to anaphylatoxin stimulation, and that IL-33 is a key regulator of mast cell responses to complement anaphylatoxins, this is likely to aggravate Th2 immune responses. This newly identified cross-regulation may be important for controlling exacerbated complement- and mast cell-dependent Th2 responses and thus provides an additional rationale for targeting anti-IL33 therapeutically in allergic diseases.
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影响因子：
8
作者：
Gour N;Smole U;Yong HM;Lewkowich IP;Yao N;Singh A;Gabrielson E;Wills-Karp M;Lajoie S
通讯作者：
Lajoie S
影响因子：
4.4
作者：
Ali, H;Ahamed, J;Patel, DD
通讯作者：
Patel, DD
影响因子：
15.9
作者：
Gaudenzio, Nicolas;Sibilano, Riccardo;Galli, Stephen J.
通讯作者：
Galli, Stephen J.
影响因子：
4.6
作者：
Cheng, Quen;Behzadi, Faraz;Hoffmann, Alexander
通讯作者：
Hoffmann, Alexander
DOI：
10.1007/978-1-0716-0696-4_19
发表时间：
2020-01-01
期刊：
BASOPHILS AND MAST CELLS, 2 EDITION
影响因子：
--
作者：
Bahri, Rajia;Bulfone-Paus, Silvia
通讯作者：
Bulfone-Paus, Silvia