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J. Biol. Chem., Vol. 283, Issue 48, 33736-33749, November 28, 2008

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NADPH Oxidase-dependent Generation of Lysophosphatidylserine Enhances Clearance of Activated and Dying Neutrophils via G2A^*

S. Courtney Frasch¹, Karin Zemski Berry, Ruby Fernandez-Boyanapalli, Hyun-Sun Jin, Christina Leslie^¶, Peter M. Henson^¶, Robert C. Murphy, and Donna L. Bratton^¶

From the Department of Pediatrics and ^¶Program in Cell Biology, National Jewish Health, Denver, Colorado 80206 and the Department of Pharmacology, University of Colorado Denver, Aurora, Colorado 80045

Exofacial phosphatidylserine (PS) is an important ligand mediating apoptotic cell clearance by phagocytes. Oxidation of PS fatty acyl groups (oxPS) during apoptosis reportedly mediates recognition through scavenger receptors. Given the oxidative capacity of the neutrophil NADPH oxidase, we sought to identify oxPS signaling species in stimulated neutrophils. Using mass spectrometry analysis, only trace amounts of previously characterized oxPS species were found. Conversely, 18:1 and 18:0 lysophosphatidylserine (lyso-PS), known bioactive signaling phospholipids, were identified as abundant modified PS species following activation of the neutrophil oxidase. NADPH oxidase inhibitors blocked the production of lyso-PS in vitro, and accordingly, its generation in vivo by activated, murine neutrophils during zymosan-induced peritonitis was absent in mice lacking a functional NADPH oxidase (gp91^phox-/-). Treatment of macrophages with lyso-PS enhanced the uptake of apoptotic cells in vitro, an effect that was dependent on signaling via the macrophage G2A receptor. Similarly, endogenously produced lyso-PS also enhanced the G2A-mediated uptake of activated PS-exposing (but non-apoptotic) neutrophils, raising the possibility of non-apoptotic mechanisms for removal of inflammatory cells during resolution. Finally, antibody blockade of G2A signaling in vivo prolonged zymosan-induced neutrophilia in wild-type mice, whereas having no effect in gp91^phox-/- mice where lyso-PS are not generated. Taken together, we show that lyso-PS are modified PS species generated following activation of the NADPH oxidase and lyso-PS signaling through the macrophage G2A functions to enhance existing receptor/ligand systems for optimal resolution of neutrophilic inflammation.

Received for publication, September 10, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI058228 (to D. L. B.), HL34303 (to D. L. B., C. C. L., and R. C. M.), and GM61031 and HL81151 (to P. M. H.). This work was also supported by a grant from the Immunodeficiency Foundation (to D. L. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and Figs. S1 and S2.

¹ To whom correspondence should be addressed: 1400 Jackson St., Denver, CO 80206. Fax: 303-398-1381; E-mail: fraschc{at}njc.org.

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