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TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase

Jie Fan1, Randall S Frey, Asrar B Malik

  • 1Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.

The Journal of Clinical Investigation
|October 17, 2003
PubMed

Insights

Neutrophil NADPH oxidase activation is crucial for Toll-like receptor 2 (TLR2) upregulation in endothelial cells. This process, driven by lipopolysaccharide (LPS) and Toll-like receptor 4 (TLR4) signaling, involves PMN oxidant signaling.

Area of Science:

  • Immunology
  • Cell Biology
  • Innate Immunity

Background:

  • Polymorphonuclear neutrophils (PMNs) interact with endothelial cells, influencing innate immune responses.
  • Toll-like receptor 2 (TLR2) upregulation is a key event in endothelial cell activation during infection.

Purpose of the Study:

  • To investigate the role of PMN NADPH oxidase in TLR2 upregulation mediated by lipopolysaccharide (LPS)-TLR4 signaling in endothelial cells.
  • To elucidate the signaling pathways involved in this cross-talk between TLR4 and TLR2.

Main Methods:

  • Utilized neutropenic mouse models and wild-type (WT) mice.
  • Co-cultured mouse lung vascular endothelial cells with PMNs.
  • Analyzed NF-kB activation, TLR2 expression, and ICAM-1 expression.
  • Investigated the impact of NADPH oxidase deficiency in PMNs.

Main Results:

  • LPS-induced TLR2 upregulation in endothelial cells is dependent on TLR4 and MyD88 signaling.
  • PMN NADPH oxidase activity is essential for LPS-induced NF-kB activation and TLR2 expression in endothelial cells.
  • PMN-derived oxidant signaling mediates the cross-talk between TLR4 and TLR2, enhancing endothelial cell activation and PMN migration.

Conclusions:

  • PMN NADPH oxidase-derived oxidant signaling plays a critical role in regulating TLR4-induced TLR2 expression in endothelial cells.
  • This pathway is a significant determinant of endothelial cell activation and immune cell recruitment during innate immune responses.

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