Leukocytes in the Vaso-Occlusive Process

Abstract

Sickle cell disease (SCD) results from a single mutation in the β-globin gene, leading to clinical manifestations that extend far beyond the mutated hemoglobin in red blood cells (RBCs). SCD is associated with a chronic inflammatory condition that, in the presence of a “second hit”, can produce vaso-occlusive crises (VOC), the major cause of morbidity and mortality of the disease. Leukocytes play an important role in the vaso-occlusive phenomenon, as suggested initially by the findings of clinical studies that high leukocyte count strongly correlates with clinical severity of the disease. Further, intravital microscopy studies in SCD mice have revealed that sickle RBCs directly interact with adherent neutrophils in post-capillary and collecting venules. These heterotypic interactions are mediated by activated α_Mβ₂ (Mac-1) integrin polarized on the leading edge of adherent neutrophils, resulting in severe VOC. A multistep and multicellular model for the vaso-occlusive process is proposed in which endothelial cells are activated by sickle RBCs and multiple inflammatory mediators, leading to the recruitment of adherent leukocytes. The recruited adherent neutrophils capture circulating sickle RBCs, resulting in reduced blood flow and vascular occlusion in the microcirculation. This model has triggered several clinical trials targeting drivers of vaso-occlusion, and suggests a major contribution of leukocytes to sickle cell VOC.