Abstract
In a recent work, we have described the kinetics among the monocyte subsets in the peripheral blood of hemolytic patients including paroxysmal nocturnal hemoglobinuria (PNH) and sickle cell disease (SCD). After engulfing Hb-activated platelets, classical monocytes (CD14+CD16−) significantly transformed into highly inflammatory (CD14+CD16hi) subsets in vitro. An estimated 40% of total circulating monocytes in PNH and 70% in SCD patients existed as CD14+CD16hi subsets. In this study, we show that the nonclassical (CD14dimCD16+) monocyte subsets are nearly absent in patients with PNH or SCD, compared to 10-12% cells in healthy individuals. In mechanism, we have described the unique role of both free Hb and nitric oxide (NO) in reducing number of nonclassical subsets more than classical monocytes. After engulfing Hb-activated platelets, the monocytes including nonclassical subsets acquired rapid cell death within 12 h in vitro. Further, the treatment to monocytes either with the secretome of Hb-activated platelets containing NO and free Hb or purified free Hb along with GSNO (a physiological NO donor) enhanced rapid cell death. Besides, our data from both PNH and SCD patients exhibited a direct correlation between intracellular NO and cell death marker 7AAD in monocytes from the peripheral blood. Our data together suggest that due to the immune surveillance nature, the nonclassical or patrolling monocytes are encountered frequently by Hb-activated platelets, free Hb, and NO in the circulation of hemolytic patients and are predisposed to die rapidly.
Highlights
In healthy individuals, peripheral blood monocytes are categorized mainly into three subsets by surface expression of CD14, a coreceptor for toll-like receptor 4 (TLR4) and CD16, a low affinity Fcγ receptor
We have reported a significant increase in intermediate monocyte subsets and a decrease in classical monocyte subsets in both paroxysmal nocturnal hemoglobinuria (PNH) and sickle cell disease (SCD) patients [34]
Our current study depicts a significant alteration in nonclassical monocyte subsets (CD14dimCD11chigh)
Summary
Peripheral blood monocytes are categorized mainly into three subsets by surface expression of CD14, a coreceptor for toll-like receptor 4 (TLR4) and CD16, a low affinity Fcγ receptor These subsets include classical CD14++CD16+ monocytes, which have high expression of CD14; nonclassical CD14+CD16++ monocytes, which have high expression of CD16 and very low levels of CD14; and intermediate/inflammatory CD14++CD16+ monocytes, which coexpress CD16 together with high levels of CD14 [1]. Activated platelets release several bioactive molecules including cytokines, chemokines, and nitric oxide (NO) that play a significant role in modulating the function of other immune cells [17, 18].
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