Multicellular and multistep model of sickle cell vaso-occlusion. Sickle cell vaso-occlusion arises from a cascade of interactions among RBCs, neutrophils, and endothelial cells. Activation of endothelial cells leads to the recruitment of neutrophils, which is initiated by rolling of neutrophils on endothelial selectins, followed by adhesion mediated by integrins. Adherent neutrophils receive a secondary wave of signals transduced through E-selectin, leading to the activation of α_Mβ₂ (Mac-1) integrin on the leading edge. Activated Mac-1 on adherent neutrophils mediates the capture of circulating sickle RBCs, producing a temporary or prolonged obstruction of venular blood flow. Circulating neutrophils exhibit considerable heterogeneity in their proinflammatory properties. Signals derived from the microbiota drive the neutrophil aging in the circulation, generating an overly active aged subset that exhibits enhanced Mac-1 activation and NETs formation. Aged neutrophils play an important role in promoting sickle cell vaso-occlusion. Currently, whether NET formation plays a role in the vaso-occlusive process remains unclear. ESL-1, E-selectin ligand-1; MADCAM-1, mucosal vascular addressin cell adhesion molecule-1; PSGL-1, P-selectin glycoprotein ligand-1; VLA-4, very late antigen-4.