Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion

Abstract

Sickle cell anemia is characterized by painful vaso-occlusive crises. It is hypothesized that monocytes are activated in sickle cell disease and can enhance vaso-occlusion by activating endothelium. To test this hypothesis, human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (MVEC) with sickle and normal mononuclear leukocytes were incubated, and endothelial activation was measured. Endothelial cells incubated with sickle mononuclear leukocytes were more activated than those incubated with normal mononuclear leukocytes, as judged by the increased endothelial expression of adhesion molecules and tissue factor and the adhesion of polymorphonuclear leukocytes (PMNL). Monocytes, not lymphocytes or platelets, were the mononuclear cells responsible for activating endothelial cells. Sickle monocytes triggered endothelial nuclear factor-kappa B (NF-κB) nuclear translocation. Cell-to-cell contact of monocytes and endothelium enhanced, but was not required for, activation. Antibodies to tumor necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β) blocked activation of the endothelium by monocytes. Peripheral blood monocytes from patients with sickle cell disease had 34% more IL-1β (P = .002) and 139% more TNF-α (P = .002) per cell than normal monocytes. Sixty percent of sickle monocytes expressed the adhesion molecule ligand CD11b on their surfaces compared with only 20% of normal monocytes (P = .002). Serum C-reactive protein, a marker of systemic inflammation, was increased 12-fold in sickle serum than in normal serum (P = .003). These results demonstrate that sickle monocytes are activated and can, in turn, activate endothelial cells. It is speculated that vascular inflammation, marked by activated monocytes and endothelium, plays a significant role in the pathophysiology of vaso-occlusion in sickle cell anemia.

Red blood cell alloimmunization is associated with lower expression of FcγR1 on monocyte subsets in patients with sickle cell disease

“…It has previously been described that CD11b expression on the monocytes of patients with SCD is significantly higher than that of race matched healthy controls . We thus compared CD11b expression on monocytes in responders and non‐responders, and found no differences between the groups (mean 37,639 ± 23,458 vs. mean 43,069 ± 17,525, p = 0.39).…”

“…Monocytes have been extensively studied in patients with SCD, with a focus on their association with inflammation and their impact on the vascular endothelium . Patients with SCD have higher monocyte counts than race matched controls, and it has been proposed that a hemolytic phenotype further increases monocyte count and activation .…”

Hyperhemolysis syndrome in sickle cell disease: case report (recurrent episode) and literature review

“…Macrophages are already activated in patients with SCD 15 . Fever is the common presenting symptom in acute HS 5,8‐10 and subclinical infection may further activate the macrophages.…”

Alloimmunization to transfused HOD red blood cells is not increased in mice with sickle cell disease

“…Additionally, increases in inflammatory cytokines and decreases in anti‐inflammatory cytokines have been reported in patients with sickle cell disease 17‐21 . Finally, patients with sickle cell disease also exhibit chronic vascular endothelial activation 22‐28 . Thus, taken together with our prior reports that inflammation enhances RBC alloimmunization in a murine model 29 and a report that inflammation may enhance RBC alloimmunization in humans, 30 it is possible that the baseline inflammation that occurs secondary to sickle cell disease pathophysiology may contribute to the high rates of RBC alloimmunization observed in patients with sickle cell disease.…”