Hepatopancreatobiliary Service, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York 10065, USA.
J Clin Invest. 2010 Feb;120(2):559-69. doi: 10.1172/JCI40008. Epub 2010 Jan 19.
TLRs are recognized as promoters of tissue damage, even in the absence of pathogens. TLR binding to damage-associated molecular patterns (DAMPs) released by injured host cells unleashes an inflammatory cascade that amplifies tissue destruction. However, whether TLRs possess the reciprocal ability to curtail the extent of sterile inflammation is uncertain. Here, we investigated this possibility in mice by studying the role of conventional DCs (cDCs) in liver ischemia/reperfusion (I/R) injury, a model of sterile inflammation. Targeted depletion of mouse cDCs increased liver injury after I/R, as assessed by serum alanine aminotransferase and histologic analysis. In vitro, we identified hepatocyte DNA as an endogenous ligand to TLR9 that promoted cDCs to secrete IL-10. In vivo, cDC production of IL-10 required TLR9 and reduced liver injury. In addition, we found that inflammatory monocytes recruited to the liver via chemokine receptor 2 were downstream targets of cDC IL-10. IL-10 from cDCs reduced production of TNF, IL-6, and ROS by inflammatory monocytes. Our results implicate inflammatory monocytes as mediators of liver I/R injury and reveal that cDCs respond to DAMPS during sterile inflammation, providing the host with protection from progressive tissue damage.
TLRs 被认为是组织损伤的促进剂，即使在没有病原体的情况下也是如此。TLR 与受损宿主细胞释放的损伤相关分子模式 (DAMPs) 结合，引发炎症级联反应，放大组织破坏。然而，TLRs 是否具有相反的能力来限制无菌性炎症的程度尚不确定。在这里，我们通过研究常规 DC（cDC）在肝脏缺血/再灌注（I/R）损伤中的作用来研究这种可能性，这是一种无菌性炎症模型。通过血清丙氨酸氨基转移酶和组织学分析评估，靶向敲除小鼠 cDC 后，I/R 后的肝损伤增加。体外，我们确定肝细胞 DNA 是 TLR9 的内源性配体，可促进 cDC 分泌 IL-10。在体内，cDC 产生的 IL-10 需要 TLR9 并减少肝损伤。此外，我们发现趋化因子受体 2 招募到肝脏的炎性单核细胞是 cDC IL-10 的下游靶点。cDC 产生的 IL-10 减少了炎性单核细胞产生的 TNF、IL-6 和 ROS。我们的研究结果表明炎性单核细胞是肝脏 I/R 损伤的介导者，并揭示了 cDC 在无菌性炎症期间对 DAMPs 的反应，为宿主提供了免受进行性组织损伤的保护。
