Identification of a key pathway required for the sterile inflammatory response triggered by dying cells
Identification of a key pathway required for the sterile inflammatory response triggered by dying cells
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DOI：
10.1038/nm1603
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发表时间：
2007-07-01
期刊：
影响因子：
82.9
通讯作者：
Rock, Kenneth L.
中科院分区：
文献类型：
--
作者：
Chen, Chun-Jen;Kono, Hajime;Rock, Kenneth L.
死亡细胞刺激炎症，这种反应被认为是许多疾病的发病机制。然而，人们对细胞死亡如何引发炎症知之甚少。我们在这里发现，对细胞损伤的急性嗜酸性炎症反应需要信号蛋白髓样分化初级反应基因88（Myd 88）。Myd 88依赖性受体对这种反应的贡献的分析显示，在Toll样受体2（Tlr 2）和Tlr 4双重缺陷的小鼠中仅轻微降低，而在缺乏Tlr 1、Tlr 3、Tlr 6、Tlr 7、Tlr 9、Tlr 11或白细胞介素-18受体（IL-18 R）的小鼠中反应正常。然而，缺乏IL-1 R的小鼠表现出对体内死亡细胞和组织损伤的嗜中性炎症反应显著降低，以及炎症的附带损伤大大降低。这种炎症反应需要IL-1 α，而非骨髓来源的细胞需要IL-1 R功能。值得注意的是，被认为对组织修复很重要的急性单核细胞对细胞死亡的反应对IL-1 R-Myd 88途径的依赖性要小得多。此外，这种途径是不需要的中性粒细胞对微生物刺激的反应。这些发现表明，在体内抑制IL-1 R-Myd 88通路可以阻断因无菌细胞死亡而发生的急性炎症损伤，并且这样做的方式可能不会损害组织修复或宿主对病原体的防御。
Dying cells stimulate inflammation, and this response is thought to contribute to the pathogenesis of many diseases. Very little has been known, however, about how cell death triggers inflammation. We found here that the acute neutrophilic inflammatory response to cell injury requires the signaling protein myeloid differentiation primary response gene 88 (Myd88). Analysis of the contribution of Myd88-dependent receptors to this response revealed only a minor reduction in mice doubly deficient in Toll-like receptor 2 (Tlr2) and Tlr4 and normal responses in mice lacking Tlr1, Tlr3, Tlr6, Tlr7, Tlr9, Tlr11 or the interleukin-18 receptor (IL-18R). However, mice lacking IL-1R showed a markedly reduced neutrophilic inflammatory response to dead cells and tissue injury in vivo as well as greatly decreased collateral damage from inflammation. This inflammatory response required IL-1 alpha, and IL-1R function was required on non-bone-marrow-derived cells. Notably, the acute monocyte response to cell death, which is thought to be important for tissue repair, was much less dependent on the IL-1R-Myd88 pathway. Also, this pathway was not required for the neutrophil response to a microbial stimulus. These findings suggest that inhibiting the IL-1R-Myd88 pathway in vivo could block the damage from acute inflammation that occurs in response to sterile cell death, and do so in a way that might not compromise tissue repair or host defense against pathogens.