Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury

Andrés Hidalgo, Jungshan Chang, Jung Eun Jang, Anna J. Peired, Elaine Y. Chiang, Paul S. Frenette

Research output: Contribution to journalArticle

206 Citations (Scopus)

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 α M Β 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 α M Β 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 α M Β 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.

Original languageEnglish
Pages (from-to)384-391
Number of pages8
JournalNature Medicine
Volume15
Issue number4
DOIs
Publication statusPublished - Apr 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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