Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury

Abstract

Selectins and their ligands mediate leukocyte rolling allowing interactions with chemokines that lead to integrin activation and arrest. Here, we demonstrate that E-selectin is critical to induce a secondary wave of activating signals transduced specifically by E-selectin ligand-1, that induces polarized, activated αMβ2 integrin clusters at the leading edge of crawling neutrophils, allowing the capture of circulating erythrocytes or platelets. In a humanized model of sickle cell disease (SCD), the capture of erythrocytes by αMβ2 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 produces vascular damage and lung injury. Inactivation of E-selectin or αMβ2 prevented tissue injury in both inflammatory models, suggesting broad implications of this paradigm in thrombo-inflammatory diseases. These results indicate that endothelial selectins can influence neutrophil behavior beyond its canonical rolling step through delayed, organ-damaging, polarized activation.

Physiological Contribution of CD44 as a Ligand for E-Selectin during Inflammatory T-Cell Recruitment

“…10,21,24 Genotypes of all mice were determined by PCR. All animals were housed at the Mount Sinai School of Medicine barrier facility.…”

“…18 Signaling through ligands for E-selectin, including PSGL-1 and ESL-1, has been shown to modulate integrin activity on neutrophils, resulting in reduced rolling velocities, 19 promotion of firm arrest, 20 and secondary capture of blood components. 21 Whether CD44 shares these properties on inflammatory lymphocytes remains unknown.…”

Abnormal modulation of cell protective systems in response to ischemic/reperfusion injury is important in the development of mouse sickle cell hepatopathy

“…In addition, the abnormally activated ET-1 system and the reduced NO bioavaibility associated with activated endothelial vascular cells, highly adherent neutrophils and dense, dehydrated sickle red cells, all participate in sickle cell-related tissue injury. 4,16,17 Although the liver is not one of the main target organs of SCD, its anatomic organization and function, characterized by a sluggish circulation, high metabolic rate and complex regulation of blood flow in the microcirculation, make this an interesting "window organ" to study the pathogenesis of sickle cell-related tissue damage.…”

Update on Acute Lung Injury and Critical Care Medicine 2009

“…In a mouse study, platelets played a critical role in neutrophilmediated lung injury from acid instillation or antibody-mediated transfusion-associated lung injury (24). Another group that used elegant imaging methods also identified an important role for platelets through interactions with neutrophils in lung and organ injury (25). Also, a comprehensive review of platelets and their role in ALI, thrombosis, and lung inflammation was published (26).…”