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Blood, 26 February 2009, Vol. 113, No. 9, pp. 2047-2055. Prepublished online as a Blood First Edition Paper on October 24, 2008; DOI 10.1182/blood-2008-05-160564. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2008-05-160564v1 113/9/2047    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fernandez-Boyanapalli, R. F. Articles by Bratton, D. L. Search for Related Content PubMed PubMed Citation Articles by Fernandez-Boyanapalli, R. F. Articles by Bratton, D. L. Related Collections Phagocytes, Granulocytes, and Myelopoiesis Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS Impaired apoptotic cell clearance in CGD due to altered macrophage programming is reversed by phosphatidylserine-dependent production of IL-4 Ruby F. Fernandez-Boyanapalli1, S. Courtney Frasch1, Kathleen McPhillips2, R. William Vandivier3, Brian L. Harry3, David W. H. Riches1, Peter M. Henson1, and Donna L. Bratton1 1 Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO; and Departments of 2 Pathology and 3 Medicine, University of Colorado Denver Health Sciences Chronic granulomatous disease (CGD) is characterized by overexuberant inflammation and autoimmunity that are attributed to deficient anti-inflammatory signaling. Although regulation of these processes is complex, phosphatidylserine (PS)–dependent recognition and removal of apoptotic cells (efferocytosis) by phagocytes are potently anti-inflammatory. Since macrophage phenotype also plays a beneficial role in resolution of inflammation, we hypothesized that impaired efferocytosis in CGD due to macrophage skewing contributes to enhanced inflammation. Here we demonstrate that efferocytosis by macrophages from CGD (gp91phox–/–) mice was suppressed ex vivo and in vivo. Alternative activation with interleukin 4 (IL-4) normalized CGD macrophage efferocytosis, whereas classical activation by lipopolysaccharide (LPS) plus interferon (IFN) had no effect. Importantly, neutralization of IL-4 in wild-type macrophages reduced macrophage efferocytosis, demonstrating a central role for IL-4. This effect was shown to involve 12/15 lipoxygenase and activation of peroxisome-proliferator activated receptor (PPAR). Finally, injection of PS (whose exposure is lacking on CGD apoptotic neutrophils) in vivo restored IL-4–dependent macrophage reprogramming and efferocytosis via a similar mechanism. Taken together, these findings support the hypothesis that impaired PS exposure on dying cells results in defective macrophage programming, with consequent efferocytic impairment and has important implications in understanding the underlying cause of enhanced inflammation in CGD. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Long-lived life: a detriment Laurence A. Boxer Blood 2009 113: 1871-1872. [Full Text] [PDF] This article has been cited by other articles: L. A. Boxer Long-lived life: a detriment Blood, February 26, 2009; 113(9): 1871 - 1872. [Full Text] [PDF] D. Sanmun, E. Witasp, S. Jitkaew, Y. Y. Tyurina, V. E. Kagan, A. Ahlin, J. Palmblad, and B. Fadeel Involvement of a functional NADPH oxidase in neutrophils and macrophages during programmed cell clearance: implications for chronic granulomatous disease Am J Physiol Cell Physiol, January 1, 2009; 297(3): C621 - C631. [Abstract] [Full Text] [PDF]

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