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Inhibits Macrophage Clearance of Apoptotic Cells via Cytosolic Phospholipase A2 and Oxidant-Dependent Mechanisms1
* Department of Pathology, University of Colorado Health Sciences Center, Denver, CO 80262;
Division of Pulmonary Medicine, Department of Medicine, and
Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206; and
Department of Physiology, Ewha Womans University College of Medicine, Seoul, Korea
Removal of apoptotic cells from inflammatory sites is an important step in the resolution of inflammation. Both murine and human macrophages stimulated with TNF-
or directly administered arachidonic acid showed an impaired ability to ingest apoptotic cells (efferocytosis). The inhibition was shown to be due to generation of reactive oxygen species, was blocked with a superoxide dismutase mimetic, MnTBAP, and was mimicked by direct addition of H2O2. To determine the mechanism of TNF--stimulated oxidant production, bone marrow-derived macrophages from gp91phox-deficient mice were examined but shown to still produce oxidants and exhibit defective apoptotic cell uptake. In contrast, a specific cytosolic phospholipase A2 inhibitor blocked the oxidant production and reversed the inhibited uptake. The suppressive effect of endogenous or exogenous oxidants on efferocytosis was mediated through activation of the GTPase, Rho. It was reversed in macrophages pretreated with C3 transferase to inactivate Rho or with an inhibitor of Rho kinase. During maturation of human monocyte-derived macrophages, only mature cells exhibited TNF--induced suppression of apoptotic cell clearance. The resistance of immature macrophages to such inhibition was shown to result not from defective generation of oxidants, but rather, from lack of response of these cells to the oxidants. Overall, the data suggest that macrophages in a TNF-- and oxidant-rich inflammatory environment are less able to remove apoptotic cells and, thereby, may contribute to the local intensity of the inflammatory response.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants GM61031, HL81151, AI058228, and HL34303.
2 J.L.K. and P.H. are senior coauthors of this work.
3 Address correspondence and reprint requests to Dr. Peter Henson, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail address: hensonp{at}njc.org
4 Abbreviations used in this paper: ROS, reactive oxygen species; HMDM, human monocyte-derived macrophage; BMDM, bone marrow-derived macrophage; DPI, diphenyleneiodonium; MnTBAP, manganese III tetrakis (5,10,15,20-benzoic acid) porphyrin; OTC, oxo-thiazolidine-carboxylic acid; DHE, dihydroethidium; C3T, C3 transferase; SOD, superoxide dismutase; cPLA2, cytosolic phospholipase A2; MAFP, methyl arachadonyl fluorophosphate.
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