Format

Send to

Choose Destination
Nat Med. 2009 Apr;15(4):384-91. doi: 10.1038/nm.1939. Epub 2009 Mar 22.

Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury.

Author information

1
Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.

Abstract

Selectins and their ligands mediate leukocyte rolling, allowing interactions with chemokines that lead to integrin activation and arrest. Here we show that E-selectin is crucial for generating a secondary wave of activating signals, transduced specifically by E-selectin ligand-1, that induces polarized, activated alpha(M)beta(2) integrin clusters at the leading edge of crawling neutrophils, allowing capture of circulating erythrocytes or platelets. In a humanized mouse model of sickle cell disease, the capture of erythrocytes by alpha(M)beta(2) microdomains leads to acute lethal vascular occlusions. In a model of transfusion-related acute lung injury, polarized neutrophils capture circulating platelets, resulting in the generation of oxidative species that produce vascular damage and lung injury. Inactivation of E-selectin or alpha(M)beta(2) prevents tissue injury in both inflammatory models, suggesting broad implications of this paradigm in thromboinflammatory diseases. These results indicate that endothelial selectins can influence neutrophil behavior beyond its canonical rolling step through delayed, organ-damaging, polarized activation.

PMID:
19305412
PMCID:
PMC2772164
DOI:
10.1038/nm.1939
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center