Oncotarget

Research Perspective: Immunology:

Kukoamine B promotes TLR4-independent lipopolysaccharide uptake in murine hepatocytes

Dong Yang, Xinchuan Zheng, Ning Wang, Shijun Fan, Yongjun Yang, Yongling Lu, Qian Chen, Xin Liu and Jiang Zheng _

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Oncotarget. 2016; 7:57498-57513. https://doi.org/10.18632/oncotarget.11292

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Abstract

Dong Yang1, Xinchuan Zheng1, Ning Wang1, Shijun Fan1, Yongjun Yang1, Yongling Lu1, Qian Chen1, Xin Liu1 and Jiang Zheng1

1 Medical Research Center, Southwest Hospital, Third Military Medical University, Chongqing, China

Correspondence to:

Jiang Zheng, email:

Xin Liu, email:

Keywords: lipopolysaccharide, kukoamine B, hepatocytes, asialoglycoprotein receptor, Immunology and Microbiology Section, Immune response, Immunity

Received: April 30, 2016 Accepted: August 11, 2016 Published: August 15, 2016

Abstract

Free bacterial lipopolysaccharide (LPS) is generally removed from the bloodstream through hepatic uptake via TLR4, the LPS pattern recognition receptor, but mechanisms for internalization and clearance of conjugated LPS are less clear. Kukoamine B (KB) is a novel cationic alkaloid that interferes with LPS binding to TLR4. In this study, KB accelerated blood clearance of LPS. KB also enhanced LPS distribution in the hepatic tissues of C57 BL/6 mice, along with LPS uptake in primary hepatocytes and HepG2 cells. By contrast, KB inhibited LPS internalization in Kupffer and RAW 264.7 cells. Loss of TLR4 did not affect LPS uptake into KB-treated hepatocytes. We also detected selective upregulation of the asialoglycoprotein receptor (ASGPR) upon KB treatment, and ASGPR colocalized with KB in cultured hepatocytes. Molecular docking showed that KB bound to ASGPR in a manner similar to GalNAc, a known ASGPR agonist. GalNAc dose-dependently reduced KB internalization, suggesting it competes with KB for ASGPR binding, and ASGPR knockdown also impaired LPS uptake into hepatocytes. Finally, while KB enhanced LPS uptake, it was protective against LPS-induced inflammation and hepatocyte injury. Our study provides a new mechanism for conjugated LPS hepatic uptake induced by the LPS neutralizer KB and mediated by membrane ASGPR binding.


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