High-Density Lipoproteins Exert Pro-inflammatory Effects on Macrophages via Passive Cholesterol Depletion and PKC-NF-κB/STAT1-IRF1 Signaling

Cell Metab. 2017 Jan 10;25(1):197-207. doi: 10.1016/j.cmet.2016.10.013. Epub 2016 Nov 17.


Membrane cholesterol modulates a variety of cell signaling pathways and functions. While cholesterol depletion by high-density lipoproteins (HDLs) has potent anti-inflammatory effects in various cell types, its effects on inflammatory responses in macrophages remain elusive. Here we show overt pro-inflammatory effects of HDL-mediated passive cholesterol depletion and lipid raft disruption in murine and human primary macrophages in vitro. These pro-inflammatory effects were confirmed in vivo in peritoneal macrophages from apoA-I transgenic mice, which have elevated HDL levels. In line with these findings, the innate immune responses required for clearance of P. aeruginosa bacterial infection in lung were compromised in mice with low HDL levels. Expression analysis, ChIP-PCR, and combinatorial pharmacological and genetic intervention studies unveiled that both native and reconstituted HDL enhance Toll-like-receptor-induced signaling by activating a PKC-NF-κB/STAT1-IRF1 axis, leading to increased inflammatory cytokine expression. HDL's pro-inflammatory activity supports proper functioning of macrophage immune responses.

Keywords: bacterial infection; high-density lipoproteins; immune response; inflammation; inflammatory signaling; macrophages; passive cholesterol depletion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Biological Transport / drug effects
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Humans
  • Inflammation / metabolism*
  • Inflammation / pathology*
  • Interferon Regulatory Factor-1 / metabolism
  • Lipoproteins, HDL / pharmacology*
  • Macrophages / metabolism*
  • Macrophages / pathology*
  • Membrane Microdomains / drug effects
  • Membrane Microdomains / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • NF-kappa B / metabolism
  • Protein Kinase C / metabolism
  • Respiratory Tract Infections / metabolism
  • Respiratory Tract Infections / microbiology
  • Respiratory Tract Infections / pathology
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Toll-Like Receptors / metabolism


  • Interferon Regulatory Factor-1
  • Lipoproteins, HDL
  • NF-kappa B
  • STAT1 Transcription Factor
  • Toll-Like Receptors
  • Cholesterol
  • Protein Kinase C