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Theranostics 2020; 10(12):5290-5304. doi:10.7150/thno.42658 This issue Cite

Research Paper

PTPROt aggravates inflammation by enhancing NF-κB activation in liver macrophages during nonalcoholic steatohepatitis

Kangpeng Jin^1,2#, Yang Liu^1,2#, Yuze Shi^3#, Haitian Zhang^1,2, YuanYuan Sun³, Guangyan Zhangyuan^1,2, Fei Wang^1,2, Weiwei Yu^1,2, Jincheng Wang^1,2, Xuewen Tao^1,2, Xin Chen^1,2, Wenjie Zhang^1,2✉, Beicheng Sun^1,2✉

1. Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
2. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, P.R. China
3. Medical School of Southeast University, Nanjing, Jiangsu Province, China, P.R.China
# These authors contributed equally to this work.

✉ Corresponding author: Beicheng Sun, Ph.D., M.D., Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China; Email: sunbcedu.cn; TEL: 86-25-83105892; FAX: 86-25-86560946 Wenjie Zhang, Ph.D., M.D., Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China;Email: drzhangwjcom; TEL: 86-025-83105892 FAX: 86-025-83105892 More

Abstract

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.

Keywords: Mitophagy, Inflammasome, Reactive oxygen species, Mitochondria, NLR family pyrin domain containing 3

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