Neutrophil activation in sickle cell disease

Abstract

Vascular occlusion is the main cause of the morbidity and mortality observed in patients with sickle cell disease (SCD). Increasing evidence indicates that (activated) neutrophils could play an important role in the initiation and propagation of vaso-occlusive processes in SCD. In this study, the activation state of neutrophils in sickle cell patients was analyzed by determining the level of expression of neutrophil antigens such as CD62L, CD11b, CD66b, CD63, and Fcgamma receptors. We also analyzed plasma levels of lactoferrin, elastase, soluble (s)CD16 (sFcgammaRIII), and serum levels of soluble (s)CD62L (sL-selectin) as neutrophil activation markers in these patients. Significant differences were observed in the activation state of neutrophils in non-symptomatic sickle cell patients compared to healthy HbAA controls as exemplified by significant decrease in L-selectin expression, enhanced expression of CD64, and increased levels of soluble markers like sL-selectin, elastase, and sCD16. During vaso-occlusive crisis the differences were even more pronounced. These results show neutrophils to be activated in sickle cell patients, suggesting a role of importance in the pathophysiology of sickle cell disease.

Inflammatory potential of neutrophils detected in sickle cell disease

“…Treatment with hydroxyurea reduces the number of circulating leukocytes correlating with improved clinical outcome [32]. Proinflammatory functions observed in SCD neutrophils include enhanced respiratory burst [14], augmented Mac-1, L-selectin, and CD64 expression [3,4,11], and increased adhesion to fibronectin [13] and inflamed endothelium during crisis [11]. The findings of this study imply that neutrophils in the blood of SCD patients have a greater potential for response to inflammatory stimulus, which leads to rapid adhesion to CD18 ligands including ICAM-1 on endothelium and ICAM-4 upregulated on SCD RBCs [33,34].…”

“…In one report, SCD neutrophils did not bind CBRM1/5, an antibody reporter of an activated epitope on Mac-1 [3]. In another study, SCD neutrophils exhibited increased adhesion to the Mac-1 ligand fibronectin compared to control [13].…”

“…Vascular occlusions (VOC) underlie most of the acute and chronic complications of sickle cell disease (SCD) and correlate with upregulation of soluble adhesion molecules and leukocyte activation [1][2][3][4]. A sequential process involving adhesion through selectins and integrins governs leukocyte recruitment to activated endothelium and to sickle red blood cells (RBC), resulting in heterotypic aggregation and VOC [5,6].…”

GTP-dependent Secretion from Neutrophils Is Regulated by Cdk5

“…4B, middle) transcripts in mouse neutrophils, the relevance of p35-associated Cdk5 activity in secretion by GTP-stimulated neutrophils was further examined using cells from p35 Ϫ/Ϫ mice and their corresponding wt. Secretion was assessed by analyzing the surface expression of CD63 and CD66b, which have been shown as effective markers of secretion from azurophil and specific granules, respectively (27)(28)(29). As shown in Fig.…”

Microvascular blood flow and stasis in transgenic sickle mice: Utility of a dorsal skin fold chamber for intravital microscopy

“…The repetitive vaso-occlusive episodes cause tissue ischemia and reperfusion injury, resulting in endothelial cell activation and inflammation [4,5]. Sickle patients have multiple indicators of an inflammatory response including elevated white counts [6][7][8][9], C-reactive protein levels [10][11][12][13], cytokines [14][15][16][17], as well as activated monocytes [13,18], neutrophils [19][20][21], platelets [18,[22][23][24][25][26][27][28], and endothelial cells [29,30] in circulation.…”