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PNAS 106 (48): 20388-20393

Copyright © 2009 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / IMMUNOLOGY

Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome

Shankar S. Iyera,b, Wilco P. Pulskensc, Jeffrey J. Sadlera,b, Loes M. Butterc, Gwendoline J. Teskec, Tyler K. Ullanda,b, Stephanie C. Eisenbarthd,e, Sandrine Florquinc, Richard A. Flavelle,f, Jaklien C. Leemansc,1,2, and Fayyaz S. Sutterwalaa,b,1,2

aDivision of Infectious Diseases and the bInflammation Program, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; cDepartment of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and dDepartment of Laboratory Medicine, eDepartment of Immunobiology, and the fHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520

Edited by Vincent T. Marchesi, Yale University School of Medicine, New Haven, CT, and approved October 14, 2009

Received for publication July 31, 2009.

Abstract: Dying cells are capable of activating the innate immune system and inducing a sterile inflammatory response. Here, we show that necrotic cells are sensed by the Nlrp3 inflammasome resulting in the subsequent release of the proinflammatory cytokine IL-1β. Necrotic cells produced by pressure disruption, hypoxic injury, or complement-mediated damage were capable of activating the Nlrp3 inflammasome. Nlrp3 inflammasome activation was triggered in part through ATP produced by mitochondria released from damaged cells. Neutrophilic influx into the peritoneum in response to necrotic cells in vivo was also markedly diminished in the absence of Nlrp3. Nlrp3-deficiency moreover protected animals against mortality, renal dysfunction, and neutrophil influx in an in vivo renal ischemic acute tubular necrosis model. These findings suggest that the inhibition of Nlrp3 inflammasome activity can diminish the acute inflammation and damage associated with tissue injury.

Key Words: caspase-1 • interleukin-1β • necrosis

Author contributions: S.S.I., W.P.P., S.F., J.C.L., and F.S.S. designed research; S.S.I., W.P.P., J.J.S., L.M.B., G.J.T., and T.K.U. performed research; S.C.E. and R.A.F. contributed new reagents/analytic tools; S.S.I., W.P.P., J.J.S., L.M.B., G.J.T., S.F., J.C.L., and F.S.S. analyzed data; and J.C.L. and F.S.S. wrote the paper.

1J.C.L. and F.S.S. contributed equally to this work.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0908698106/DCSupplemental.

2To whom correspondence may be addressed. E-mail: j.c.leemans{at}amc.uva.nl or fayyaz-sutterwala{at}uiowa.edu

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