Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death.
Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death.
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DOI：
10.4049/jimmunol.0902485
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发表时间：
2010-04-15
期刊：
影响因子：
--
通讯作者：
Rock KL
中科院分区：
文献类型：
--
作者：
Kono H;Karmarkar D;Iwakura Y;Rock KL
细胞死亡会引发强烈的炎症反应。我们之前已经证明，这种反应依赖于IL-α。在这里，我们研究了宿主用来感知细胞死亡、产生IL-α的细胞机制，以及IL-β在这一反应中的作用。在几乎所有接受检查的病例中，刺激死亡诱导的炎症反应的IL-1来自宿主，而不是死亡的细胞。在这种情况下，宿主骨髓来源的细胞是炎症反应所需的IL-α的关键来源。在CD11b启动子驱动的白喉毒素受体转基因小鼠中，有条件的细胞耗竭和重建表明宿主巨噬细胞在炎症反应的产生中发挥了重要作用，并是所需IL-α的来源。此外，我们发现IL-β在死亡诱导的炎症反应中起作用，这种细胞因子是由骨髓来源的和抗辐射的宿主细胞产生的。这些发现的一个例外是，当树突状细胞被注射到小鼠体内时，它们提供了刺激炎症的部分IL-1，这是通过观察树突状细胞是活的还是坏死的来观察的。综上所述，这些发现表明，巨噬细胞作为主要哨兵发挥着关键作用，需要通过启动炎症反应的方式来感知和报告细胞死亡。它们完成这一重要任务的一个关键方法是产生启动炎症反应所需的IL-α。
Cell death provokes a robust inflammatory response. We have previously shown that this response is dependent on IL-α. Here we investigate the cellular mechanism used by a host to sense cell death, produce IL-α and also the role of IL-β in this response. In almost all cases examined, the IL-1 that stimulated the death-induced inflammatory response came from the host rather than the cell that was dying. In these situations, host bone marrow-derived cells were the key source of the IL-α that was required for the inflammatory response. Conditional cellular depletion and reconstitution in CD11b promoter- driven diphtheria toxin receptor transgenic mice revealed that host macrophages played an essential role in the generation of the inflammatory response and were the source of the required IL-α. In addition, we found a role for IL-β in the death-induced inflammatory response and that this cytokine was generated by both bone marrow-derived and radioresistant host cells. The one exception to these findings was that when dendritic cells were injected into mice, they provided a portion of the IL-1 that stimulated inflammation, and this was observed whether the dendritic cells were live or necrotic. Together, these findings demonstrate that macrophages play a key role as the primary sentinels that are required to sense and report cell death in ways that initiate the inflammatory response. One key way they accomplish this important task is by producing IL-α that is needed to initiate the inflammatory response.
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