Dysfunctional, pro-inflammatory HDL directly upregulates monocyte PDGFRβ, chemotaxis and TNFα production.
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.
Skaggs
Brian J
BJ
Division of Rheumatology, David Geffen UCLA School of Medicine, 32-59 Rehab Center, Los Angeles, CA 90095, USA. bskaggs@mednet.ucla.edu
Hahn
Bevra H
BH
Sahakian
Lori
L
Grossman
Jennifer
J
McMahon
Maureen
M
D000328:Adult; D016632:Apolipoprotein A-I / Q000737:chemistry; D001549:Benzamides; D002340:Carotid Artery Diseases / Q000097:blood / Q000209:etiology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects*; D002784:Cholesterol / Q000097:blood; D051152:Clusterin / Q000737:chemistry; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006331:Heart Diseases / Q000453:epidemiology; D006801:Humans; D000068877:Imatinib Mesylate; D008075:Lipoproteins, HDL / Q000097:blood / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D008875:Middle Aged; D018716:Molecular Mimicry; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics*; D012307:Risk Factors; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D016632:Apolipoprotein A-I; D001549:Benzamides; C111835:CCL2 protein, human; C495242:CLU protein, human; D018932:Chemokine CCL2; D051152:Clusterin; D008075:Lipoproteins, HDL; D010455:Peptides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D000068877:Imatinib Mesylate; D002784:Cholesterol; D020797:Receptor, Platelet-Derived Growth Factor beta