Importance of PLC-dependent PI3K/AKT and AMPK signaling in RANTES/CCR5 mediated macrophage chemotaxis

Hung Che Chien, Pei Chi Chan, Chuan Chou Tu, Yuan Ji Day, Li Man Hung, Chi Chang Juan, Yu Feng Tian*, Po Shiuan Hsieh

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

17 Scopus citations

Abstract

Regulated upon activation, normal T cell expressed, and secreted (RANTES), also known as chemokine ligand 5 (CCL5), has been reported to facilitate macrophage migration, which plays a crucial role in tissue inflammation. The aim of this study is to investigate the characteristics and underlying mechanism of RANTES on macrophage chemotaxis under physiological and pathological conditions. The study was conducted on macrophage RAW264.7 cell and bone marrow-derived macrophages (BMDM) isolated from CCL receptor 5 (CCR5) knockout mice. The macrophage migration and glucose uptake was assessed in time and dose dependent manners. Moreover, reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis were used to characterize mRNA and protein level related to the underlying mechanism. The present result showed that the maraviroc, a selective CCR5 inhibitor, dose-dependently suppressed RANTES-induced rapid increases in glucose uptake and cell migration in RAW264.7 cells. Similar effects were observed in the BMDM isolated from CCR5 knockout mice compared with wild type control. RANTES treatment promptly enhanced membrane glucose transporter 1 (GLUT1) expression, glucose uptake as well as phosphorylation of AKT on Thr308, Ser473 within min and has prolonged effect on phosphorylation of AMP-activated protein kinase (AMPK) on Thr172, which were abrogated by maraviroc, CCR5 siRNA or phospholipase C (PLC) inhibitor in RAW264.7 cells. Inhibition of PI3K and AMPK by LY294002 and Compound C significantly suppress RANTES-stimulated macrophage glucose uptake and migration, respectively. RANTES has biphasic effect on activating PLC signaling including prompt action on PI3K/AKT phosphorylation and prolong action on AMPK phosphorylation via CCR5 which leads to increased GLUT1-mediated glucose uptake and macrophage migration under physiopathological states.

Original languageEnglish
Pages (from-to)266-279
Number of pages14
JournalChinese Journal of Physiology
Volume61
Issue number5
DOIs
StatePublished - 2018

Bibliographical note

Publisher Copyright:
© 2018 by The Chinese Physiological Society.

Keywords

  • CCR5
  • Macrophage chemotaxis
  • Phospholipase C
  • RANTES

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