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Myeloid related proteins activate Toll-like receptor 4 in human acute coronary syndromes

Keiko Yonekawa1, Michel Neidhart, Lukas A Altwegg

  • 1Department of Cardiology, CardioVascular Center, University Hospital Zurich, Switzerland.

Atherosclerosis
|July 26, 2011
PubMed
Abstract

Insights

Myeloid related proteins (MRP) 8 and 14 activate Toll-like receptor (TLR) 4 on monocytes in acute coronary syndromes (ACS). This MRP8/14-TLR4 pathway drives TNFα release, suggesting a therapeutic target for coronary occlusion.

Area of Science:

  • Immunology
  • Cardiovascular Medicine
  • Molecular Biology

Background:

  • Toll-like receptor 4 (TLR4) expression is elevated on monocytes within thrombi of acute coronary syndrome (ACS) patients.
  • Myeloid-related proteins (MRP) 8 and 14, typically found in neutrophils and monocytes, activate TLR4 during sepsis.
  • This study investigates if MRPs mediate pro-inflammatory responses via TLR4 in ACS patient-derived monocytes from thrombi.

Purpose of the Study:

  • To determine if myeloid-related proteins (MRP) 8 and 14 activate Toll-like receptor 4 (TLR4) on monocytes from acute coronary syndrome (ACS) thrombi.
  • To investigate the role of the MRP8/14-TLR4 pathway in TNFα release from ACS patient monocytes.
  • To explore this pathway as a potential therapeutic target in ACS.

Main Methods:

  • Analysis of coronary thrombi and peripheral blood from 27 ACS patients.
  • Isolation and incubation of CD14(+) monocytes with TLR ligands (PM3SKA, LPS), MRP8, MRP14, or MRP8/14 complex.
  • Inhibition of TLR4 using anti-TLR4 antibodies (HTA125) and endotoxin inhibition with polymyxin B (PMB).
  • Measurement of TNFα release via ELISA and TLR4 expression via flow cytometry on stimulated monocytes.

Main Results:

  • MRP8 and MRP8/14 significantly increased TNFα release from CD14(+) monocytes, with higher levels from thrombus-derived cells compared to peripheral blood cells.
  • LPS, MRP8, and MRP8/14 stimulated TNFα release, which was inhibited by HTA125, indicating TLR4-dependency.
  • MRP8/14 enhanced TLR4 expression on monocytes from thrombi but not from peripheral blood.

Conclusions:

  • The MRP8/14 complex acts as a specific ligand for TLR4 on monocytes in ACS, inducing TNFα release.
  • This MRP8/14-TLR4 pathway, similar to sepsis, increases TLR4 expression in thrombi and is implicated in coronary occlusion pathogenesis.
  • The identified pathway represents a potential novel therapeutic target for ACS treatment.

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