Inflammasome components coordinate autophagy and pyroptosis as macrophage responses to infection.
Inflammasome components coordinate autophagy and pyroptosis as macrophage responses to infection.
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DOI：
10.1128/mbio.00620-12
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发表时间：
2013-02-12
期刊：
影响因子：
6.4
通讯作者：
Swanson MS
中科院分区：
文献类型：
--
作者：
Byrne BG;Dubuisson JF;Joshi AD;Persson JJ;Swanson MS
当微生物污染巨噬细胞细胞质时，白细胞经历促炎性死亡，其由结合并激活半胱天冬酶-1的含核苷酸结合结构域、富含亮氨酸重复序列的蛋白质（NLR蛋白）启动。我们报告说，这些炎性体成分也调节自噬，一个囊泡途径，以消除胞质碎片。在响应感染鞭毛虫嗜肺军团菌，C57 BL/6 J小鼠巨噬细胞配备半胱天冬酶-1和NLR蛋白NAIP 5和NLRC 4刺激自噬体周转。炎性小体组装的第二个触发因素K+流出也迅速激活产生半胱天冬酶-1的巨噬细胞中的自噬。自噬保护受感染的巨噬细胞免于焦亡，因为当自噬被3-甲基腺嘌呤或Atg 4蛋白酶抑制剂抑制时，caspase-1依赖性细胞死亡更频繁地发生。因此，除了协调焦亡之外，炎性小体的（前）半胱天冬酶-1蛋白和NLR组分都使巨噬细胞能够募集自噬，这是一种提高触发促炎性白细胞死亡所需的污染物阈值的处置途径。重要性先天免疫领域的一项令人兴奋的发展是认识到巨噬细胞会利用自噬来保护其细胞质免受感染。营养缺乏长期以来一直被认为会诱导自噬;感染如何触发这种处理途径是一个活跃的研究领域。自噬是由许多细胞内病原体所遇到的，这些病原体已知会触发焦亡，一种当含有核苷酸结合结构域、富含亮氨酸重复序列的蛋白质（NLR蛋白）激活炎性复合物内的半胱天冬酶-1时引发的炎性细胞死亡。因此，我们测试的假设，NLR蛋白和半胱天冬酶-1也协调自噬作为细胞质感染的障碍。通过利用经典的细菌和小鼠遗传学和自噬的动力学测定，我们首次证明，当面临胞质污染时，原代小鼠巨噬细胞不仅依赖于NLR蛋白NAIP 5和NLRC 4，而且依赖于（前）caspase-1蛋白来启动快速的自噬反应，从而避免促炎细胞死亡。在先天免疫领域的一个令人兴奋的发展是认识到巨噬细胞争取自噬以保护其细胞质免受感染。长期以来，人们都知道营养缺乏会诱导自噬;感染如何触发这种处置途径是一个活跃的研究领域。自噬是由许多细胞内病原体所遇到的，这些病原体已知会触发焦亡，一种当含有核苷酸结合结构域、富含亮氨酸重复序列的蛋白质（NLR蛋白）激活炎性复合物内的半胱天冬酶-1时引发的炎性细胞死亡。因此，我们测试的假设，NLR蛋白和半胱天冬酶-1也协调自噬作为细胞质感染的障碍。通过利用经典的细菌和小鼠遗传学和自噬的动力学测定，我们首次证明，当面临胞质污染时，原代小鼠巨噬细胞不仅依赖于NLR蛋白NAIP 5和NLRC 4，而且依赖于（前）caspase-1蛋白来启动快速的自噬反应，从而避免促炎细胞死亡。
When microbes contaminate the macrophage cytoplasm, leukocytes undergo a proinflammatory death that is initiated by nucleotide-binding-domain-, leucine-rich-repeat-containing proteins (NLR proteins) that bind and activate caspase-1. We report that these inflammasome components also regulate autophagy, a vesicular pathway to eliminate cytosolic debris. In response to infection with flagellate Legionella pneumophila, C57BL/6J mouse macrophages equipped with caspase-1 and the NLR proteins NAIP5 and NLRC4 stimulated autophagosome turnover. A second trigger of inflammasome assembly, K+ efflux, also rapidly activated autophagy in macrophages that produced caspase-1. Autophagy protects infected macrophages from pyroptosis, since caspase-1-dependent cell death occurred more frequently when autophagy was dampened pharmacologically by either 3-methyladenine or an inhibitor of the Atg4 protease. Accordingly, in addition to coordinating pyroptosis, both (pro-) caspase-1 protein and NLR components of inflammasomes equip macrophages to recruit autophagy, a disposal pathway that raises the threshold of contaminants necessary to trigger proinflammatory leukocyte death. IMPORTANCE An exciting development in the innate-immunity field is the recognition that macrophages enlist autophagy to protect their cytoplasm from infection. Nutrient deprivation has long been known to induce autophagy; how infection triggers this disposal pathway is an active area of research. Autophagy is encountered by many of the intracellular pathogens that are known to trigger pyroptosis, an inflammatory cell death initiated when nucleotide-binding-domain-, leucine-rich-repeat-containing proteins (NLR proteins) activate caspase-1 within inflammasome complexes. Therefore, we tested the hypothesis that NLR proteins and caspase-1 also coordinate autophagy as a barrier to cytosolic infection. By exploiting classical bacterial and mouse genetics and kinetic assays of autophagy, we demonstrate for the first time that, when confronted with cytosolic contamination, primary mouse macrophages rely not only on the NLR proteins NAIP5 and NLRC4 but also on (pro-)caspase-1 protein to mount a rapid autophagic response that wards off proinflammatory cell death. An exciting development in the innate-immunity field is the recognition that macrophages enlist autophagy to protect their cytoplasm from infection. Nutrient deprivation has long been known to induce autophagy; how infection triggers this disposal pathway is an active area of research. Autophagy is encountered by many of the intracellular pathogens that are known to trigger pyroptosis, an inflammatory cell death initiated when nucleotide-binding-domain-, leucine-rich-repeat-containing proteins (NLR proteins) activate caspase-1 within inflammasome complexes. Therefore, we tested the hypothesis that NLR proteins and caspase-1 also coordinate autophagy as a barrier to cytosolic infection. By exploiting classical bacterial and mouse genetics and kinetic assays of autophagy, we demonstrate for the first time that, when confronted with cytosolic contamination, primary mouse macrophages rely not only on the NLR proteins NAIP5 and NLRC4 but also on (pro-)caspase-1 protein to mount a rapid autophagic response that wards off proinflammatory cell death.