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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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 29, 2008 Accepted October 3, 2008 Impaired apoptotic cell clearance in CGD due to altered macrophage programming is reversed by phosphatidylserine-dependent production of IL-4 Ruby F Fernandez-Boyanapalli, S. Courtney Frasch, Kathleen McPhillips, R. William Vandivier, Brian L. Harry, David WH. Riches, Peter M. Henson, and Donna L Bratton* Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO, United States Department of Pathology,, University of Colorado Denver Health Sciences, Denver, CO, United States Department of Medicine, University of Colorado Denver Health Sciences, Denver, CO, United States * Corresponding author; email: brattond{at}njc.org. Chronic granulomatous disease (CGD) is characterized by over-exuberant inflammation and autoimmunity that are attributed to deficient anti-inflammatory signaling. While regulation of these processes is complex, posphatidylserine (PS) dependent recognition and removal of apoptotic cells (efferocytosis) by phagocytes is 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 IL-4 normalized CGD macrophage efferocytosis while classical activation by LPS+IFN had no effect. Importantly, neutralization of IL-4 in wildtype macrophages reduced macrophage efferocytosis, demonstrating a central role for IL-4. This effect was shown to involve 12/15 lipoxygenase and activation of 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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