Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion
Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion
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DOI：
10.1172/jci40008
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发表时间：
2010-02-01
影响因子：
15.9
通讯作者：
DeMatteo, Ronald P.
中科院分区：
文献类型：
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作者：
Bamboat, Zubin M.;Ocuin, Lee M.;DeMatteo, Ronald P.
TLR被认为是组织损伤的促进剂，即使在没有病原体的情况下。TLR与受损宿主细胞释放的损伤相关分子模式（DAMP）结合，释放出放大组织破坏的炎症级联反应。然而，TLR是否具有减少无菌炎症程度的相互能力尚不确定。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（一种无菌炎症模型）中的作用来研究小鼠中的这种可能性。通过血清丙氨酸氨基转移酶和组织学分析评估，小鼠cDC的靶向耗竭增加了I/R后的肝损伤。在体外，我们鉴定肝细胞DNA作为TLR 9的内源性配体，其促进cDC分泌IL-10。在体内，cDC产生IL-10需要TLR 9并减少肝损伤。此外，我们发现通过趋化因子受体2募集到肝脏的炎性单核细胞是cDC IL-10的下游靶标。来自cDC的IL-10减少炎性单核细胞的TNF、IL-6和ROS的产生。我们的研究结果表明炎性单核细胞是肝脏I/R损伤的介质，并揭示了cDC在无菌炎症过程中对DAMPS产生应答，为宿主提供保护，使其免受进行性组织损伤。
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.