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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2071.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

High-Density Lipoprotein Reduces the Human Monocyte Inflammatory Response

Andrew J. Murphy; Kevin J. Woollard; Anh Hoang; Nigora Mukhamedova; Roslynn A. Stirzaker; Sally P.A. McCormick; Alan T. Remaley; Dmitri Sviridov; Jaye Chin-Dusting

From the Laboratories of Vascular Pharmacology (A.J.M., K.J.W., J.C.D.) and Lipoproteins and Atherosclerosis (A.H., N.M., D.S.), Baker Heart Research Institute, Melbourne, Victoria, Australia; Molecular Medicine (R.A.S.), The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; the Department of Biochemistry (S.P.A.M.), University of Otago, Dunedin, Otago, New Zealand; and the Lipoprotein Metabolism Section (A.T.R.), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Md.

Correspondence to Jaye Chin-Dusting, Baker Heart Research Institute, PO Box 6492, St Kilda Rd Central, Victoria 8008 Australia. E-mail jaye.chin-dusting{at}baker.edu.au

Objective— Whereas the anti–inflammatory effects of high-density lipoprotein (HDL) on endothelial cells are well described, such effects on monocytes are less studied.

Methods and Results— Human monocytes were isolated from whole blood followed by assessment of CD11b activation/expression and cell adhesion under shear-flow. HDL caused a dose-dependent reduction in the activation of CD11b induced by PMA or receptor-dependent agonists. The constituent of HDL responsible for the antiinflammatory effects on CD11b activation was found to be apolipoprotein A-I (apoA-I). Cyclodextrin, but not cyclodextrin/cholesterol complex, also inhibited PMA-induced CD11b activation implicating cholesterol efflux as the main mechanism. This was further confirmed with the demonstration that cholesterol content of lipid rafts diminished after treatment with the cholesterol acceptors. Blocking ABCA1 with an anti-ABCA1 antibody abolished the effect of apoA-I. Furthermore, monocytes derived from a Tangier disease patient definitively confirmed the requirement of ABCA1 in apoA-I–mediated CD11b inhibition. The antiinflammatory effects of apoA-I were also observed in functional models including cell adhesion to an endothelial cell monolayer, monocytic spreading under shear flow, and transmigration.

Conclusions— HDL and apoA-I exhibit an antiinflammatory effect on human monocytes by inhibiting activation of CD11b. ApoA-I acts through ABCA1, whereas HDL may act through several receptors.

High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) exhibit a potent antiinflammatory effect on human monocytes, inhibiting expression of the adhesion molecule CD11b, an effect mediated through cholesterol efflux. The effect of apoA-I was dependent on ABCA1, whereas HDL may act through multiple receptors.

Key Words: apolipoprotein A-I • CD11b • monocyte • ABCA1 • Tangier

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