Published online before print April 14, 2005, doi: 10.1161/01.ATV.0000166517.18801.a7
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Phagocytosis of Apoptotic Cells by Macrophages Is Impaired in Atherosclerosis
From the Division of Pharmacology (D.M.S., G.R.Y.D.M., M.M.K., A.G.H., W.M.), University of Antwerp, Wilrijk, Belgium; and the Department of Pathology (M.M.K.), AZ Middelheim, Antwerp, Belgium
Correspondence to Dorien M. Schrijvers, Division of Pharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium. E-mail dorien.schrijvers{at}ua.ac.be
Objective— Apoptotic cell death has been demonstrated in advanced human atherosclerotic plaques. Apoptotic cells (ACs) should be rapidly removed by macrophages, otherwise secondary necrosis occurs, which in turn elicits inflammatory responses and plaque progression. Therefore, we investigated the efficiency of phagocytosis of ACs by macrophages in atherosclerosis.
Methods and Results— Human endarterectomy specimens and human tonsils were costained for CD68 (macrophages) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) (apoptosis). Free and phagocytized ACs were counted in both tissues. The ratio of free versus phagocytized AC was 19-times higher in human atherosclerotic plaques as compared with human tonsils, indicating a severe defect in clearance of AC. Impaired phagocytosis of AC was also detected in plaques from cholesterol-fed rabbits and did not further change with plaque progression. In vitro experiments with J774 or peritoneal mouse macrophages showed that several factors caused impaired phagocytosis of AC including cytoplasmic overload of macrophages with indigestible material (beads), free radical attack, and competitive inhibition among oxidized red blood cells, oxidized low-density lipoprotein and ACs for the same receptor(s) on the macrophage.
Conclusion— Our data demonstrate that phagocytosis of ACs is impaired in atherosclerotic plaques, which is at least partly attributed to oxidative stress and cytoplasmic saturation with indigestible material.
Determination of phagocytosis efficiency of apoptotic cells (ACs) revealed a marked impairment of clearance of ACs in atherosclerotic plaques as compared with tonsils. In vitro studies indicated oxidative stress factors present in the plaque as the major contributors to this impairment.
Key Words: atherosclerosis • apoptosis • macrophages • oxidative stress • phagocytosis
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