Dysfunctional, Pro-Inflammatory HDL Directly Upregulates Monocyte PDGFRβ, Chemotaxis and TNFα Production

Clin Immunol. 2010 Oct;137(1):147-56. doi: 10.1016/j.clim.2010.06.014. Epub 2010 Jul 15.

Abstract

Accelerated atherosclerosis is a major co-morbid condition in autoimmune diseases. Monocytes are the main immune cell involved in atherosclerosis initiation. We hypothesized that dysfunctional, pro-inflammatory HDL (piHDL), which occurs in approximately half of SLE patients, might directly influence monocyte gene expression and function. SLE subjects were stratified into three groups: 1) carotid artery plaque+piHDL+,2) plaque-piHDL+,and 3) plaque-piHDL- (n=18/group). PDGFRβ was upregulated in primary monocytes from plaque+piHDL+patients and in THP-1 cells acutely treated in vitro with piHDL compared to normal HDL. THP-1 chemotaxis was enhanced after treatment with piHDL versus normal HDL. Abnormal migration was restored to normal levels by treatment with imatinib or an apoJ mimetic peptide. Increased piHDL-mediated TNFα protein levels were reduced with both inhibitors. Dysfunctional piHDL directly influences expression of a small number of transcripts and proteins, and piHDL inhibition through reducing piHDL oxidation or blocking PDGFRβ kinase activity restored normal monocyte chemotaxis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apolipoprotein A-I / chemistry
  • Benzamides
  • Carotid Artery Diseases / blood
  • Carotid Artery Diseases / etiology
  • Carotid Artery Diseases / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Chemotaxis / drug effects*
  • Cholesterol / blood
  • Clusterin / chemistry
  • Female
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Heart Diseases / epidemiology
  • Humans
  • Imatinib Mesylate
  • Lipoproteins, HDL / blood
  • Lipoproteins, HDL / pharmacology*
  • Lupus Erythematosus, Systemic / blood
  • Lupus Erythematosus, Systemic / complications
  • Lupus Erythematosus, Systemic / diagnosis
  • Lupus Erythematosus, Systemic / metabolism*
  • Middle Aged
  • Molecular Mimicry
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Peptides / pharmacology
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / pharmacology
  • Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
  • Receptor, Platelet-Derived Growth Factor beta / genetics*
  • Risk Factors
  • Severity of Illness Index
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Apolipoprotein A-I
  • Benzamides
  • CCL2 protein, human
  • CLU protein, human
  • Chemokine CCL2
  • Clusterin
  • Lipoproteins, HDL
  • Peptides
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Tumor Necrosis Factor-alpha
  • Imatinib Mesylate
  • Cholesterol
  • Receptor, Platelet-Derived Growth Factor beta