Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Biol. Chem. 281 (29): 20055-20067

© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

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

Marija Cvetanovic{ddagger}12, Justin E. Mitchell{ddagger}1, Vimal Patel§, Benjamin S. Avner{ddagger}, Yan Su, Paul T. van der Saag||, Pamela L. Witte, Stefano Fiore**, Jerrold S. Levine§, , and David S. Ucker{ddagger}3

{ddagger}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

Abstract: 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. Revision received 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}

Adenovirus E1B 19-Kilodalton Protein Modulates Innate Immunity through Apoptotic Mimicry.
J. R. Radke, F. Grigera, D. S. Ucker, J. L. Cook, and M. J. Imperiale (2014)
J. Virol. 88, 2658-2669
   Abstract »    Full Text »    PDF »
The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation.
S. Pereira-Lopes, T. Celhar, G. Sans-Fons, M. Serra, A.-M. Fairhurst, J. Lloberas, and A. Celada (2013)
J. Immunol. 191, 6128-6135
   Abstract »    Full Text »    PDF »
P2X7 Receptor-mediated Scavenger Activity of Mononuclear Phagocytes toward Non-opsonized Particles and Apoptotic Cells Is Inhibited by Serum Glycoproteins but Remains Active in Cerebrospinal Fluid.
B. J. Gu, J. A. Duce, V. A. Valova, B. Wong, A. I. Bush, S. Petrou, and J. S. Wiley (2012)
J. Biol. Chem. 287, 17318-17330
   Abstract »    Full Text »    PDF »
Recognition-dependent Signaling Events in Response to Apoptotic Targets Inhibit Epithelial Cell Viability by Multiple Mechanisms: IMPLICATIONS FOR NON-IMMUNE TISSUE HOMEOSTASIS.
V. A. Patel, L. Feng, D. J. Lee, D. Massenburg, G. Pattabiraman, A. Antoni, J. H. Schwartz, W. Lieberthal, J. Rauch, D. S. Ucker, et al. (2012)
J. Biol. Chem. 287, 13761-13777
   Abstract »    Full Text »    PDF »
Externalized Glycolytic Enzymes Are Novel, Conserved, and Early Biomarkers of Apoptosis.
D. S. Ucker, M. R. Jain, G. Pattabiraman, K. Palasiewicz, R. B. Birge, and H. Li (2012)
J. Biol. Chem. 287, 10325-10343
   Abstract »    Full Text »    PDF »
The danger model in deciphering autoimmunity.
A. A. Tveita (2010)
Rheumatology 49, 632-639
   Abstract »    Full Text »    PDF »
Recognition of Apoptotic Cells by Epithelial Cells: CONSERVED VERSUS TISSUE-SPECIFIC SIGNALING RESPONSES.
V. A. Patel, D. J. Lee, L. Feng, A. Antoni, W. Lieberthal, J. H. Schwartz, J. Rauch, D. S. Ucker, and J. S. Levine (2010)
J. Biol. Chem. 285, 1829-1840
   Abstract »    Full Text »    PDF »
Suicidal Membrane Repair Regulates Phosphatidylserine Externalization during Apoptosis.
B. Mirnikjoo, K. Balasubramanian, and A. J. Schroit (2009)
J. Biol. Chem. 284, 22512-22516
   Abstract »    Full Text »    PDF »
Ly6Clow Monocytes Differentiate into Dendritic Cells and Cross-Tolerize T Cells through PDL-1.
Y. Peng, Y. Latchman, and K. B. Elkon (2009)
J. Immunol. 182, 2777-2785
   Abstract »    Full Text »    PDF »
Sumoylation of Peroxisome Proliferator-Activated Receptor {gamma} by Apoptotic Cells Prevents Lipopolysaccharide-Induced NCoR Removal from {kappa}B Binding Sites Mediating Transrepression of Proinflammatory Cytokines.
C. Jennewein, A.-M. Kuhn, M. V. Schmidt, V. Meilladec-Jullig, A. von Knethen, F. J. Gonzalez, and B. Brune (2008)
J. Immunol. 181, 5646-5652
   Abstract »    Full Text »    PDF »
N-acetyl Cysteine Protects Pulp Cells from Resin Toxins in vivo.
A. Paranjpe, E.C. Sung, N.A. Cacalano, W.R. Hume, and A. Jewett (2008)
Journal of Dental Research 87, 537-541
   Abstract »    Full Text »    PDF »
Apoptosis in the lung: induction, clearance and detection.
P. M. Henson and R. M. Tuder (2008)
Am J Physiol Lung Cell Mol Physiol 294, L601-L611
   Abstract »    Full Text »    PDF »
Complement Receptor 3 Ligation of Dendritic Cells Suppresses Their Stimulatory Capacity.
E. M. Behrens, U. Sriram, D. K. Shivers, M. Gallucci, Z. Ma, T. H. Finkel, and S. Gallucci (2007)
J. Immunol. 178, 6268-6279
   Abstract »    Full Text »    PDF »
Nitrosative Stress Inhibits the Aminophospholipid Translocase Resulting in Phosphatidylserine Externalization and Macrophage Engulfment: IMPLICATIONS FOR THE RESOLUTION OF INFLAMMATION.
Y. Y. Tyurina, L. V. Basova, N. V. Konduru, V. A. Tyurin, A. I. Potapovich, P. Cai, H. Bayir, D. Stoyanovsky, B. R. Pitt, A. A. Shvedova, et al. (2007)
J. Biol. Chem. 282, 8498-8509
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882