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J. Biol. Chem., Vol. 281, Issue 29, 20055-20067, July 21, 2006

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Specific Recognition of Apoptotic Cells Reveals a Ubiquitous and Unconventional Innate Immunity^*

Marija Cvetanovic¹², Justin E. Mitchell¹, Vimal Patel, Benjamin S. Avner, Yan Su^¶, Paul T. van der Saag^||, Pamela L. Witte^¶, Stefano Fiore^**, Jerrold S. Levine, and David S. Ucker³

From the Department of Microbiology and Immunology, Section of Nephrology, Department of Medicine, and ^**Section of Rheumatology, Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois 60612, the ^¶Immunology and Aging Program, Department of Cell Biology, Neurology and Anatomy, Loyola University Chicago, Maywood, Illinois 60153, and the ^||Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht 3584 CT, The Netherlands

The purpose of physiological cell death is the noninflammatory clearance of cells that have become inappropriate or nonfunctional. Consistent with this function, the recognition of apoptotic cells by professional phagocytes, including macrophages and dendritic cells, triggers a set of potent anti-inflammatory responses manifest on multiple levels. The immediate-early inhibition of proinflammatory cytokine gene transcription in the phagocyte is a proximate consequence of recognition of the apoptotic corpse, independent of subsequent engulfment and soluble factor involvement. Here, we show that recognition is linked to a characteristic signature of responses, including MAPK signaling events and the ablation of proinflammatory transcription and cytokine secretion. Specific recognition and response occurs without regard to the origin (species, tissue type, or suicidal stimulus) of the apoptotic cell and does not involve Toll-like receptor signaling. These features mark this as an innate immunity fundamentally distinct from the discrimination of "self" versus "other" considered to be the hallmark of conventional immunity. This profound unconventional innate immune discrimination of effete from live cells is as ubiquitous as apoptotic cell death itself, manifest by professional and nonprofessional phagocytes and nonphagocytic cell types alike. Innate apoptotic immunity provides an intrinsic anti-inflammatory circuit that attenuates proinflammatory responses dynamically and may act systemically as a powerful physiological regulator of immunity.

Received for publication, April 24, 2006 , and in revised form, May 8, 2006.

^* This work was supported by National Institutes of Health Grants AG024234 and DK59793 (to D. S. U. 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 Both 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 S. Wolcott, Chicago, IL 60612. Tel.: 312-413-1102; Fax: 312-413-7385; E-mail: duck{at}uic.edu.

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