Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury.
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.
Hidalgo
Andrés
A
Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Chang
Jungshan
J
Jang
Jung-Eun
JE
Peired
Anna J
AJ
Chiang
Elaine Y
EY
Frenette
Paul S
PS
D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D019040:E-Selectin / Q000502:physiology*; D004912:Erythrocytes / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology* / Q000517:prevention & control*; D019041:L-Selectin / Q000235:genetics / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000502:physiology; D021962:Membrane Microdomains / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014947:Wounds and Injuries / Q000503:physiopathology
D019040:E-Selectin; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin