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J. Biol. Chem., Vol. 282, Issue 11, 8498-8509, March 16, 2007

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Nitrosative Stress Inhibits the Aminophospholipid Translocase Resulting in Phosphatidylserine Externalization and Macrophage Engulfment

IMPLICATIONS FOR THE RESOLUTION OF INFLAMMATION^*

Yulia Y. Tyurina, Liana V. Basova, Nagarjun V. Konduru, Vladimir A. Tyurin, Ala I. Potapovich, Peter Cai, Hülya Bayir, Detcho Stoyanovsky^¶, Bruce R. Pitt, Anna A. Shvedova^||, Bengt Fadeel^**, and Valerian E. Kagan¹

From the Center for Free Radical and Antioxidant Health, Departments of Environmental and Occupational Health, Pharmacology, Critical Care Medicine, ^¶Surgery, and Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, ^||National Institute of Occupational Safety and Health, Morgantown, West Virginia 26505, and ^**Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden

Macrophage recognition of apoptotic cells depends on externalization of phosphatidylserine (PS), which is normally maintained within the cytosolic leaflet of the plasma membrane by aminophospholipid translocase (APLT). APLT is sensitive to redox modifications of its -SH groups. Because activated macrophages produce reactive oxygen and nitrogen species, we hypothesized that macrophages can directly participate in apoptotic cell clearance by S-nitrosylation/oxidation and inhibition of APLT causing PS externalization. Here we report that exposure of target HL-60 cells to nitrosative stress inhibited APLT, induced PS externalization, and enhanced recognition and elimination of "nitrosatively" modified cells by RAW 264.7 macrophages. Using S-nitroso-L-cysteine-ethyl ester (SNCEE) and S-nitrosoglutathione (GSNO) that cause intracellular and extracellular trans-nitrosylation of proteins, respectively, we found that SNCEE (but not GSNO) caused significant S-nitrosylation/oxidation of thiols in HL-60 cells. SNCEE also strongly inhibited APLT, activated scramblase, and caused PS externalization. However, SNCEE did not induce caspase activation or nuclear condensation/fragmentation suggesting that PS externalization was dissociated from the common apoptotic pathway. Dithiothreitol reversed SNCEE-induced S-nitrosylation, APLT inhibition, and PS externalization. SNCEE but not GSNO stimulated phagocytosis of HL-60 cells. Moreover, phagocytosis of target cells by lipopolysaccharide-stimulated macrophages was significantly suppressed by an NO^. scavenger, DAF-2. Thus, macrophage-induced nitrosylation/oxidation plays an important role in cell clearance, and hence in the resolution of inflammation.

Received for publication, July 21, 2006 , and in revised form, January 16, 2007.

^* This work was supported by National Institutes of Health Grants HL70755, HL070807, U19 AI068021, and ES09648, National Institute of Occupational Safety and Health Grants OH008282 and AHA0535365N, the Swedish Research Council, and the Human Frontier Science Program. 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 To whom correspondence should be addressed. Tel.: 412-624-9479; Fax: 412-624-9361; E-mail: kagan{at}pitt.edu.

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