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Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
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Multi-hit inhibition of circulating and cell-associated components of the toll-like receptor 4 pathway by oxidized

Elena von Schlieffen1, Olga V Oskolkova, Gernot Schabbauer

  • 1Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.

Arteriosclerosis, Thrombosis, and Vascular Biology
|December 30, 2008
PubMed
Abstract

Insights

Oxidized phospholipids (OxPLs) inhibit toll-like receptor 4 (TLR4) activation by lipopolysaccharide (LPS). These findings reveal OxPLs as endogenous inhibitors of TLR4, acting through multiple mechanisms.

Area of Science:

  • Immunology
  • Lipidomics
  • Molecular Biology

Background:

  • Oxidized phospholipids (OxPLs) are key lipid mediators in atherosclerosis.
  • OxPLs exhibit context-dependent pro- and anti-inflammatory activities.
  • Mechanisms underlying OxPLs' effects on inflammation are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which OxPLs modulate toll-like receptor 4 (TLR4) activation by lipopolysaccharide (LPS).

Main Methods:

  • Utilized multiple cell types and inflammatory gene expression analysis.
  • Investigated OxPLs' effects on LPS-induced TLR4 activation.
  • Assessed OxPLs' impact on LPS-binding protein (LBP) and CD14 interactions.
  • Examined OxPLs' effects on synthetic TLR4 agonist E6020-induced activation.

Main Results:

  • OxPLs do not stimulate TLR4 but inhibit LPS-induced inflammatory responses.
  • OxPLs bind to LBP and CD14, preventing LPS recognition and subsequent TLR4 activation.
  • OxPLs also inhibit LBP- and CD14-independent TLR4 activation, targeting cell-associated steps.

Conclusions:

  • OxPLs inhibit LPS action through a multi-hit mechanism.
  • OxPLs act as endogenous inhibitors of TLR4.
  • These inhibitory effects are likely induced by oxidative stress.

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