The binding capability of plasma phospholipid transfer protein, but not HDL pool size, is critical to repress LPS induced inflammation.

Yang Yu,Shucun Qin,Bin Li,Xian-Cheng Jiang,Yanan Zhao,Shuai Liu,Yingjie Cui,Hao Wang,Shoudong Guo,Peng Jiao,Xiangjian Zhang,Guohua Song,Tian Luo

doi:10.1038/srep20845

Yang Yu, Shucun Qin + Show 11 more

Open Access

https://doi.org/10.1038/srep20845

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Abstract

Phospholipid transfer protein (PLTP) participates in high density lipoprotein (HDL) metabolism. Increased plasma PLTP activity was observed in lipopolysaccharide (LPS) triggered acute inflammatory diseases. This study aimed to determine the exact role of PLTP in LPS induced inflammation. HDL pool size was shrunk both in PLTP deficient mice (PLTP−/−) and PLTP transgenic mice (PLTP-Tg). PLTP displayed a strong protective effect on lethal endotoxemia in mice survival study. Furthermore, after LPS stimulation, the expression of pro-inflammatory cytokines were increased in bone marrow derived macrophage (BMDM) from PLTP−/−, while decreased in BMDM from PLTP-Tg compared with BMDM from wild-type mice (WT). Moreover, LPS induced nuclear factor kappa-B (NFκB) activation was enhanced in PLTP−/− BMDM or PLTP knockdown RAW264.7. Conversely, PLTP overexpression countered the NFκB activation in LPS challenged BMDM. Additionally, the activation of toll like receptor 4 (TLR4) induced by LPS showed no alteration in PLTP−/− BMDM. Finally, PLTP could bind to LPS, attenuate the pro-inflammatory effects of LPS, and improve the cell viability in vitro. To sum up, these findings elucidated that PLTP repressed LPS induced inflammation due to extracellular LPS binding capability, and the protective effects were not related to HDL pool size in mice.

Highlights

Transporter A1 (ABCA1)- Janus kinase-2 (JAK2)- signal transducer and activator of transcription 3 (STAT3) pathways[6,14], suggesting that extracellular effects might be the major manner of PLTP involved in LPS induced inflammatory responses
Plasma PLTP activity and High density lipoprotein (HDL) were determined in PLTP transgenic mice (PLTP-Tg), wild type mice (WT), and PLTP− /− prior to LPS injection
Plasma PLTP activity was almost absent in PLTP− /−, while moderately enhanced in PLTP-Tg compared with WT. (Fig. 1A) As is shown in Fig. 1B,C, the cholesterol level and the apoAI level of HDL were decreased both in PLTP-Tg and PLTP− /− compared with WT

Summary

Introduction

Transporter A1 (ABCA1)- Janus kinase-2 (JAK2)- signal transducer and activator of transcription 3 (STAT3) pathways[6,14], suggesting that extracellular effects might be the major manner of PLTP involved in LPS induced inflammatory responses. The major plasma contributor to PLTP activity is macrophage, which plays critical roles in LPS induced inflammatory responses by involving the initiation or restraint of inflammation[15]. Considering the increasing plasma PLTP activity in patients with endotoxemia or sepsis, we hypothesized that PLTP play key protective roles in LPS induced inflammatory responses. We investigated the effects of PLTP expression on mice survival rate of lethal endotoxemia and the role of PLTP on LPS induced NFκ B activation in macrophage

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