Lipocalin-2 expressed in innate immune cells is an endogenous inhibitor of inflammation in murine nephrotoxic serum nephritis.
Lipocalin-2 expressed in innate immune cells is an endogenous inhibitor of inflammation in murine nephrotoxic serum nephritis.
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DOI：
10.1371/journal.pone.0067693
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Theurl I
中科院分区：
文献类型：
--
作者：
Eller K;Schroll A;Banas M;Kirsch AH;Huber JM;Nairz M;Skvortsov S;Weiss G;Rosenkranz AR;Theurl I
脂质运载蛋白-2（Lcn-2）参与不同的过程，如急性肾损伤或细菌宿主防御。本研究旨在评价Lcn-2在肾毒性血清肾炎（NTS）中的功能作用。由于Lcn-2在肾小管上皮细胞以及先天免疫细胞如巨噬细胞和多形核中性粒细胞（PMN）中表达，我们在野生型（WT）、Lcn-2敲除（KO）小鼠和WT/Lcn-2 KO嵌合体中诱导NTS。与WT小鼠相比，缺乏Lcn-2的小鼠表现出更多的肾小球损伤，蛋白尿和间质白细胞积聚增加。嵌合体能够表达LCN-2在巨噬细胞和中性粒细胞，但不是在上皮细胞被发现开发NTS与野生型对照。相比之下，在先天免疫细胞中没有表达的在肾小管上皮细胞中表达Lcn-2的嵌合体由于协同凋亡减少而增加了NTS，但增加了坏死和损伤相关分子模式（DAMP）的形成，如肾脏中的高迁移率族蛋白1（HMGB-1）。体内阻断HMGB-1（一种Toll样受体（TLR）-2激动剂）可显著降低Lcn-2基因敲除小鼠的炎症和NTS。同时，发现TLR-2信号转导在体外驱动Lcn-2转录。总之，先天免疫细胞中表达的Lcn-2通过诱导协同凋亡和抑制HMGB-1的形成，从而通过TLR-2信号传导限制细胞因子产生，在NTS中具有保护作用。同时，Lcn-2的TLR-2依赖性转录是NTS中炎症的内源性抑制剂。
Lipocalin-2 (Lcn-2) is involved in divergent processes such as acute kidney injury or bacterial host defence. Our study was designed to evaluate the functional role of Lcn-2 in nephrotoxic serum nephritis (NTS). Since Lcn-2 is expressed in tubular epithelial cells as well as in cells of innate immunity such as macrophages and polymorphonuclear neutrophils (PMN), we induced NTS in wild-type (WT), Lcn-2 knock-out (KO) mice and WT/Lcn-2 KO chimeras. Mice lacking Lcn-2 exhibited more glomerular damage with increased proteinuria and interstitial leukocyte accumulation compared to WT mice. Chimeras able to express Lcn-2 in macrophages and PMN but not in epithelial cells were found to develop NTS comparable to wild-type controls. In contrast, chimeras expressing Lcn-2 in tubular epithelial cells with no expression in innate immune cells developed increased NTS due to decreased concerted apoptosis but increased necrosis and formation of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB-1) in the kidney. In vivo blockade of HMGB-1, a toll-like receptor (TLR)-2 agonist, significantly reduced inflammation and NTS in Lcn-2 knock-out mice. In parallel, TLR-2 signalling was found to drive Lcn-2 transcription in vitro. Taken together, Lcn-2 expressed in innate immune cells is protective in NTS by inducing concerted apoptosis and inhibiting the formation of HMGB-1 thereby limiting cytokine production via TLR-2 signalling. In parallel, TLR-2 dependent transcription of Lcn-2 is an endogenous inhibitor of inflammation in NTS.