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Science 330 (6002): 362-366

Copyright © 2010 by the American Association for the Advancement of Science

Intravascular Danger Signals Guide Neutrophils to Sites of Sterile Inflammation

Braedon McDonald,1 Keir Pittman,1 Gustavo B. Menezes,1,* Simon A. Hirota,2 Ingrid Slaba,1 Christopher C. M. Waterhouse,1,3 Paul L. Beck,2,4 Daniel A. Muruve,1,4 Paul Kubes1,{dagger}

Abstract: Neutrophils are recruited from the blood to sites of sterile inflammation, where they contribute to wound healing but may also cause tissue damage. By using spinning disk confocal intravital microscopy, we examined the kinetics and molecular mechanisms of neutrophil recruitment to sites of focal hepatic necrosis in vivo. Adenosine triphosphate released from necrotic cells activated the Nlrp3 inflammasome to generate an inflammatory microenvironment that alerted circulating neutrophils to adhere within liver sinusoids. Subsequently, generation of an intravascular chemokine gradient directed neutrophil migration through healthy tissue toward foci of damage. Lastly, formyl-peptide signals released from necrotic cells guided neutrophils through nonperfused sinusoids into the injury. Thus, dynamic in vivo imaging revealed a multistep hierarchy of directional cues that guide neutrophil localization to sites of sterile inflammation.

1 Immunology Research Group, University of Calgary, Alberta T2N 4N1, Canada.
2 Gastrointestinal Research Group, Snyder Institute of Infection, Immunity and Inflammation, University of Calgary, Alberta T2N 4N1, Canada.
3 Department of Pediatrics, Division of Pediatric Gastroenterology, University of Calgary, Alberta T2N 4N1, Canada.
4 Department of Medicine, University of Calgary, Alberta T2N 4N1, Canada.

* Present address: Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Brazil.

{dagger} To whom correspondence should be addressed. E-mail: pkubes{at}ucalgary.ca

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