Targeting Neutrophil Adhesive Events to Address Vaso-Occlusive Crisis in Sickle Cell Patients

Abstract

Neutrophils are essential to protect the host against invading pathogens but can promote disease progression in sickle cell disease (SCD) by becoming adherent to inflamed microvascular networks in peripheral tissue throughout the body. During the inflammatory response, leukocytes extravasate from the bloodstream using selectin adhesion molecules and migrate to sites of tissue insult through activation of integrins that are essential for combating pathogens. However, during vaso-occlusion associated with SCD, neutrophils are activated during tethering and rolling on selectins upregulated on activated endothelium that line blood vessels. Recently, we reported that recognition of sLex on L-selectin by E-selectin during neutrophil rolling initiates shear force resistant catch-bonds that facilitate tethering to endothelium and activation of integrin bond clusters that anchor cells to the vessel wall. Evidence indicates that blocking this important signaling cascade prevents the congestion and ischemia in microvasculature that occurs from neutrophil capture of sickled red blood cells, which are normally deformable ellipses that flow easily through small blood vessels. Two recently completed clinical trials of therapies targeting selectins and their effect on neutrophil activation in small blood vessels reveal the importance of mechanoregulation that in health is an immune adaption facilitating rapid and proportional leukocyte adhesion, while sustaining tissue perfusion. We provide a timely perspective on the mechanism underlying vaso-occlusive crisis (VOC) with a focus on new drugs that target selectin mediated integrin adhesive bond formation.

P‐ and E‐ selectin in venous thrombosis and non‐venous pathologies

“…Membrane P-selectin forms dimers or oligomers to increase leukocyte membrane binding leading to the strong inflammatory and thrombotic responses, where sP-selectin is present as a monomer that is not sufficient to interact with its functional ligands. 27,28 sP-selectin is derived primarily from the proteolytic cleavage of transmembrane P-selectin, shed from activated platelets and endothelial cells. High levels of sP-selectin are associated with VTE and have been proposed as a biomarker with better diagnostic performance than Ddimer where it performed favorably compared with D-dimer when combined with the Wells Score.…”

“…Although it is the membrane associated P‐selectin which primarily contributes to the pathogenesis of DVT, its soluble form has been evaluated in several studies as a biomarker for VTE. Membrane P‐selectin forms dimers or oligomers to increase leukocyte membrane binding leading to the strong inflammatory and thrombotic responses, where sP‐selectin is present as a monomer that is not sufficient to interact with its functional ligands 27,28 …”

Extracellular Vesicles in Sickle Cell Disease: A Promising Tool

“…Upon rolling, these neutrophils exhibit active integrin that allow their full arrest. This adhesion in post-capillary venules causes trapping of platelets, other neutrophils, and above all RBCs, which lead to the occurrence of a vascular occlusion [ 106 ]. The key role of neutrophils is highlighted by the absolute contraindication of myeloid growth factors such as granulocyte macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) in SCD patients [ 107 , 108 , 109 , 110 ].…”

Integrin Regulators in Neutrophils

“…In the cascade, neutrophils first roll on the vascular endothelium by interacting with endothelial selectins using P-selectin glycoprotein ligand-1 (PSGL-1) [12,13]. When neutrophils encounter endothelial chemokines during rolling, integrins on neutrophils are activated, and neutrophils firmly adhere, which we call arrest [14]. After arrest, neutrophils can spread on and neutrophils firmly adhere, which we call arrest [14].…”

“…When neutrophils encounter endothelial chemokines during rolling, integrins on neutrophils are activated, and neutrophils firmly adhere, which we call arrest [14]. After arrest, neutrophils can spread on and neutrophils firmly adhere, which we call arrest [14]. After arrest, neutrophils can spread on the endothelium, perform trans-endothelium migration (TEM) [9], and migrate to the site of infection or inflammation [15,16].…”