Priming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes In Vitro.
Priming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes In Vitro.
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DOI：
10.3389/fimmu.2020.565924
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发表时间：
2020
影响因子：
7.3
通讯作者：
Lopez-Castejon G
中科院分区：
文献类型：
--
作者：
Gritsenko A;Yu S;Martin-Sanchez F;Diaz-Del-Olmo I;Nichols EM;Davis DM;Brough D;Lopez-Castejon G
白细胞介素(IL)-18和IL-1β是强效的促炎细胞因子，有助于类风湿关节炎和阿尔茨海默病等炎症。它们是作为无活性前体产生的，在感知损伤或致病信号时被称为炎症小体的大分子复合物激活。NLRP3炎性小体的激活被认为需要一个引发NLRP3和IL-1β基因上调的启动步骤，以及NLRP3翻译后的许可。随后的激活步骤导致复合物的组装，并通过caspase-1将pro-IL-18和pro-IL-1β切割成成熟形式，允许它们释放。在这里，我们发现人类单核细胞，而不是单核细胞衍生的巨噬细胞，能够在没有启动的情况下形成典型的NLRP3炎症小体。NLRP3激活剂尼日利亚霉素在未启动的环境下引起组成性表达IL-18的加工和释放。这是由依赖于K+和Cl−外排的典型NLRP3炎性体介导的，并导致ASC寡聚化、caspase-1和Gasdermin-D （GSDMD）裂解。NLRP3抑制剂MCC950和NLRP3缺失会导致IL-18释放受损，但GSDMD缺失也会导致IL-18释放受损，这表明焦亡是IL-18释放的机制。这项工作强调了NLRP3炎症小体在人类单核细胞中缺乏启动的情况下组装的准备性，因此有助于在IL-1β尚未产生时炎症反应的早期阶段。在研究NLRP3激活机制时，考虑非启动环境是很重要的，以免掩盖在没有启动刺激的情况下发生的途径，这可能只会增强这种反应。
Interleukin (IL)-18 and IL-1β are potent pro-inflammatory cytokines that contribute to inflammatory conditions such as rheumatoid arthritis and Alzheimer’s disease. They are produced as inactive precursors that are activated by large macromolecular complexes called inflammasomes upon sensing damage or pathogenic signals. NLRP3 inflammasome activation is regarded to require a priming step that causes NLRP3 and IL-1β gene upregulation, and also NLRP3 post-translational licencing. A subsequent activation step leads to the assembly of the complex and the cleavage of pro-IL-18 and pro-IL-1β by caspase-1 into their mature forms, allowing their release. Here we show that human monocytes, but not monocyte derived macrophages, are able to form canonical NLRP3 inflammasomes in the absence of priming. NLRP3 activator nigericin caused the processing and release of constitutively expressed IL-18 in an unprimed setting. This was mediated by the canonical NLRP3 inflammasome that was dependent on K+ and Cl− efflux and led to ASC oligomerization, caspase-1 and Gasdermin-D (GSDMD) cleavage. IL-18 release was impaired by the NLRP3 inhibitor MCC950 and by the absence of NLRP3, but also by deficiency of GSDMD, suggesting that pyroptosis is the mechanism of release. This work highlights the readiness of the NLRP3 inflammasome to assemble in the absence of priming in human monocytes and hence contribute to the very early stages of the inflammatory response when IL-1β has not yet been produced. It is important to consider the unprimed setting when researching the mechanisms of NLRP3 activation, as to not overshadow the pathways that occur in the absence of priming stimuli, which might only enhance this response.
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影响因子：
7
作者：
Barker BR;Taxman DJ;Ting JP
通讯作者：
Ting JP
影响因子：
30.5
作者：
Baroja-Mazo, Alberto;Martin-Sanchez, Fatima;Pelegrin, Pablo
通讯作者：
Pelegrin, Pablo
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44.1
作者：
Gong, Yi-Nan;Wang, Xiaoming;Shao, Feng
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Shao, Feng
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8.8
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Fang J;Muto T;Kleppe M;Bolanos LC;Hueneman KM;Walker CS;Sampson L;Wellendorf AM;Chetal K;Choi K;Salomonis N;Choi Y;Zheng Y;Cancelas JA;Levine RL;Starczynowski DT
通讯作者：
Starczynowski DT
影响因子：
64.8
作者：
Ding, Jingjin;Wang, Kun;Shao, Feng
通讯作者：
Shao, Feng