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J. Biol. Chem., Vol. 281, Issue 9, 5718-5725, March 3, 2006
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Department of Microbiology and Immunology, ¶Section of Nephrology, Department of Medicine,||Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612, the Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07214, the **Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520
The role of the presumptive phosphatidylserine receptor (PSR) in the recognition and engulfment of apoptotic cells, and the antiinflammatory response they exert, has been of great interest. Genetic deficiency of PSR in the mouse is lethal perinatally, and results to date have been ambiguous with regard to the phagocytic and inflammatory phenotypes associated with that deficiency. Recently, we found that the specific functional recognition of apoptotic cells is a ubiquitous property of virtually all cell types, including mouse embryo fibroblasts, and reflects an innate immunity that discriminates live from effete cells. Taking advantage of this property of fibroblasts, we generated, PSR+/+, PSR+/-, and PSR-/- fibroblast cell lines to examine definitively the involvement of PSR in apoptotic recognition and inflammatory modulation. Our data demonstrate that PSR-deficient cells are fully competent to recognize, engulf, and respond to apoptotic cells. Signal transduction in the responder cells, including the activation of Akt and Rac1, is unimpaired in the absence of PSR. We confirm as well that PSR is localized predominantly to the nucleus. However, it does not play a role in pro-inflammatory transcription or in the anti-inflammatory modulation of that transcriptional response triggered by apoptotic cells. We conclude that PSR is not involved generally in either specific innate recognition or engulfment of apoptotic cells.
Received for publication, September 6, 2005 , and in revised form, November 7, 2005.
* This work was supported by Grants AG024234, GM55760, and DK59793 from theNational Institutes of Health (to D. S. U., R. B. B., and J. S. L., respectively) and by a Young Investigator Award from the National Kidney Foundation of Illinois (to J. S. L.). 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 These authors contributed equally to this work.
2 Present address: Dept. of Neurology, Northwestern University School of Medicine, Chicago, IL 60611.
3 To whom correspondence should be addressed: Dept. of Microbiology and Immunology (MC 790), University of Illinois College of Medicine, 835 South Wolcott, Chicago, IL 60612. Tel.: 312-413-1102; Fax: 312-413-7385; E-mail: duck{at}uic.edu.
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