A Fluorescent Reporter Mouse for Inflammasome Assembly Demonstrates an Important Role for Cell-Bound and Free ASC Specks during In Vivo Infection.
A Fluorescent Reporter Mouse for Inflammasome Assembly Demonstrates an Important Role for Cell-Bound and Free ASC Specks during In Vivo Infection.
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DOI：
10.1016/j.celrep.2016.06.011
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发表时间：
2016-07-12
期刊：
影响因子：
8.8
通讯作者：
Golenbock DT
中科院分区：
文献类型：
--
作者：
Tzeng TC;Schattgen S;Monks B;Wang D;Cerny A;Latz E;Fitzgerald K;Golenbock DT
炎性体活化与许多疾病有关。然而，激活炎性体复合物的体内检测一直受到缺乏工具的限制。我们开发了异位表达荧光接头蛋白ASC（含有caspase募集结构域的凋亡相关斑点样蛋白）的转基因小鼠，并表征了原代细胞和组织中组装炎性体复合物（“斑点”）的形成。除了造血细胞外，我们发现肺组织中的基质群在流感感染的早期阶段形成斑点，而髓细胞在两天后形成斑点。在腹膜炎和B群链球菌感染模型中，中性粒细胞在感染早期形成斑点的比例较高，而树突状细胞在较晚的时间点形成斑点。此外，形成斑点的细胞在体内发生焦亡，并大量释放斑点到细胞外环境。这些数据强调了游离斑点在体内炎症过程中的重要性。激活炎性体复合物的体内检测一直受到缺乏工具的限制。在这里，Tzeng等人开发了一种表达ASC荧光蛋白（ASC-黄嘌呤）的报告鼠模型。用炎性小体激活剂处理的小鼠显示ASC聚集增加，表明炎性小体途径被激活。
Inflammasome activation is associated with numerous diseases. However, in vivo detection of the activated inflammasome complex has been limited by a dearth of tools. We developed transgenic mice that ectopically express the fluorescent adaptor protein, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and characterized the formation of assembled inflammasome complexes (“specks”) in primary cells and tissues. In addition to hematopoietic cells, we found that a stromal population in the lung tissues forms specks during the early phase of influenza infection whereas myeloid cells showed speck formation after two days. In a peritonitis and Group B streptococcus infection models, a higher percentage of neutrophils formed specks at early phases of infection, while dendritic cells formed specks at later time points. Furthermore, speck-forming cells underwent pyroptosis, and extensive release of specks to the extracellular milieu in vivo. These data underscore the importance of free specks during inflammatory processes in vivo. In vivo detection of the activated inflammasome complex has been limited by a dearth of tools. Here, Tzeng et al. have developed a reporter mouse model expressing ASC fluorescent protein (ASC-citrine). Mice treated with inflammasome activators showed increased ASC aggregation, indicating the activation of inflammasome pathways.