PTPROt aggravates inflammation by enhancing NF-κB activation in liver macrophages during nonalcoholic steatohepatitis
PTPROt aggravates inflammation by enhancing NF-κB activation in liver macrophages during nonalcoholic steatohepatitis
复制标题
PTPROt 通过增强非酒精性脂肪性肝炎期间肝脏巨噬细胞中 NF-κB 的激活来加重炎症
DOI：
10.7150/thno.42658
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Sun, Beicheng
中科院分区：
文献类型：
--
作者：
Jin, Kangpeng;Liu, Yang;Sun, Beicheng
基本原理：炎症在非酒精性脂肪性肝炎（NASH）的进展中起着至关重要的作用。蛋白酪氨酸磷酸酶受体O型截短亚型（PTPROt）是一种完整的膜蛋白，已在破骨细胞、巨噬细胞和B淋巴细胞中鉴定。然而，炎症和NASH之间的关系在很大程度上是未知的。在此，我们的目的是研究PTPROt在NASH进展中的功能。方法：采用野生型（WT）、PTPRO基因敲除小鼠，分别通过西方饮食（WD）和蛋氨酸胆碱缺乏饮食（MCD）建立NASH小鼠模型。另外，在BMT小鼠中建立MCD诱导的NASH模型。此外，我们测定了没有脂肪变性、患有单纯性脂肪变性和患有NASH的人类受试者的肝巨噬细胞中PTPROt的表达，以证实PTPROt和NASH之间的关系。还进行了体外测定以研究PTPROt在NASH进展中的分子作用。结果如下：人类样本和动物模型结果表明，在NASH进展期间，肝脏巨噬细胞中的PTPROt增加，并且与NASH的程度正相关。我们的动物模型还表明，肝巨噬细胞中的PTPROt可以增强NF-κB信号通路的激活，其诱导参与炎症反应的基因的转录。此外，PTPROt通过增加NF-κB信号通路的激活，促进促氧化基因的转录并抑制抗氧化和保护基因，从而导致活性氧（ROS）水平升高和线粒体受损。这触发了NLRP 3-IL 1 β轴，并导致炎症反应增强。值得注意的是，PTPROt通过促进线粒体自噬部分限制炎症和ROS产生，线粒体自噬参与该模型中的负反馈回路。结论：我们的数据有力地表明，PTPROt在NASH期间通过肝脏巨噬细胞中的NF-κB信号通路在炎症中起双重作用。需要进一步的研究来探索通过PTPROt的治疗策略和预防这种常见的肝脏疾病。
Rationale: Inflammation plays a crucial role in the progression of nonalcoholic steatohepatitis (NASH). Protein tyrosine phosphatase receptor type O truncated isoform (PTPROt) is an integral membrane protein that has been identified in osteoclasts, macrophages, and B lymphocytes. However, its relationship between inflammation and NASH is largely unknown. Herein, we aimed to study the function of PTPROt in NASH progression. Methods: We established a NASH mouse model in wild-type (WT), PTPRO knockout mice by western diet (WD) and methionine-choline-deficient diet (MCD). In addition, MCD-induced NASH model was established in BMT mice. Moreover, we determined the expression of PTPROt in liver macrophages in human subjects without steatosis, with simple steatosis, and with NASH to confirm the relationship between PTPROt and NASH. In vitro assays were also performed to study the molecular role of PTPROt in NASH progression. Results: Human samples and animal model results illustrated that PTPROt is increased in liver macrophages during NASH progression and is positively correlated with the degree of NASH. Our animal model also showed that PTPROt in liver macrophages can enhance the activation of the NF-κB signaling pathway, which induces the transcription of genes involved in the inflammatory response. Moreover, PTPROt promotes the transcription of pro-oxidant genes and inhibits antioxidant and protective genes via increased activation of the NF-κB signaling pathway, thereby causing an increased level of reactive oxygen species (ROS) and damaged mitochondria. This triggers the NLRP3-IL1β axis and causes a heightened inflammatory response. Notably, PTPROt partially limits inflammation and ROS production by promoting mitophagy, which participates in a negative feedback loop in this model. Conclusions: Our data strongly indicate that PTPROt plays a dual role in inflammation via the NF-κB signaling pathway in liver macrophages during NASH. Further studies are required to explore therapeutic strategies and prevention of this common liver disease through PTPROt.