Activated monocytes and platelet-monocyte aggregates in patients with sickle cell disease*

Abstract

Tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) increase endothelial surface receptors that mediate the adherence of sickle erythrocytes to the endothelium. Increased circulating levels of these cytokines have been found in patients with sickle cell disease (SCD). Monocytes are a source of both of these inflammatory mediators; we therefore determined whether circulating monocytes were activated in SCD, as defined by intracellular expression of these cytokines. Blood was also assayed for the presence of platelet-monocyte aggregates (PMAs), as platelet adherence is one possible mechanism for monocyte activation. The median percentages of monocytes expressing intracellular TNF-alpha and IL-1beta in SCD patients were 6.8 (2.8-17.3) [median (range)] and 14.1 (1.3-44.8), respectively. In African-American controls the corresponding percentages were 0.3 (0.1-0.5) and 0.4 (0.1-3.0), and in Caucasians 0.2 (0.1-0.5) and 0.8 (0.8-1.9) (P < 0.001, Kruskal-Wallis). The mean percentage (+/- SD) of PMA was 14.0 +/- 8.3 for Caucasian controls, 25.7 +/- 7.3 for African-American controls, and 45.7 +/- 21.6 for patients with SCD (P < 0.001, RM ANOVA; P < 0.05, Newman-Keuls posthoc test). We conclude that there are increased circulating PMAs and monocyte activation in patients with SCD.

Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy

“…The gene expressions of TNF-␣ and IL-8 genes were found to be significantly higher in SCA MC, and levels of IL-8 mRNA were higher in the neutrophils of SCA individuals. Results indicate that MC and neutrophils are important for inflammatory molecule production in SCA, supporting previous reports showing that monocytes appear to circulate in an activated state in SCD patients and probably serve as a source of the increased plasma levels of TNF-␣ [25,26]. Notably, a substantial variation in cytokine levels is observed in our population and in other populations of SCA individuals; for example, those patients that presented the most elevated levels of TNF-␣ were not the same individuals as those that demonstrated the highest levels of plasma IL-8.…”

Inflammatory potential of neutrophils detected in sickle cell disease

“…Previous studies have shown higher incidence of platelet-erythrocyte [21,22] and platelet-monocyte [23] aggregates, as well as lower total leukocyte, neutrophil, and platelet counts [24] in African-Americans than in Caucasians. Further investigation of the ethnic differences in inflammatory markers and responses may elucidate the mechanisms by which African-Americans experience a higher incidence of and mortality due to chronic vascular diseases such as hypertension, diabetes, cardiovascular, and renal disease [25,26].…”

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.…”