Vessel-housekeeping monocytes: towards a novel target in sickle cell disease
Francesca Vinchi, PhD
Lindsley F. Kimball Research Institute (LFKRI), New York Blood Center - NYBC, New York, USA.
Recent insights in the pathomechanisms of painful vaso-occlusive crises (VOC), a hallmark of sickle cell disease (SCD), have unraveled the critical role of hemoglobin-derived heme released during hemolytic events, as an "alarmin" capable of activating the immune system and damaging the vascular endothelium.
In a recent issue of Blood, Yunfeng Liu and colleagues explored the vascular-protective role of a specific subset of endothelial patrolling monocytes (PMos) in SCD.
This monocyte subset is characterized by elevated levels of the heme-degrading enzyme HO-1 (HO-1hi) and reduced expression of inflammatory cytokines in SCD. Using labeling experiments, the authors demonstrated that a direct interaction of monocytes with endothelial cells (ECs) exposed to heme, followed by phagocytosis of heme-injured ECs, is a requisite for HO-1hi PMo generation.
Importantly, the HO-1hi PMo subset was reduced in SCD patients experiencing recent or recurrent VOC events, suggesting that inappropriately low HO-1hi PMos is a predisposing factor to VOC in SCD. The enhanced heme-induced vascular stasis of sickle erythrocytes in a PMo-ablated mouse line highlighted the critical "housekeeping" function of HO-1hi PMos in the removal of hemolysis-injured ECs in the SCD vasculature and in lowering VOC risk.
Future studies will uncover in the near future the potential of PMo manipulation for therapeutic applications in SCD.
Figure 1. Hypothetical anti-VOC function of HO-1hi PMos. Hemolytic events lead to the release of free hemoglobin-derived heme, causing endothelial cell (EC) activation and damage. The authors propose that increased expression of adhesion molecules and phosphatidylserine (PS) on ECs promotes the recruitment of patrolling monocytes (PMos) along the endothelial lining. PMos remove heme-injured ECs and cell debris, switching into a subset of high HO-1 (HO-1hi) expressing monocytes with anti-inflammatory and housekeeping properties. Elevated HO-1hi PMos decrease (a), whereas low HO-1hi PMos increase (b) the risk of VOC in SCD.
Yunfeng Liu et al., HO-1hi patrolling monocytes protect against vaso-occlusion in sickle cell disease. Blood 2018 Feb 2. pii: blood-2017-12-819870. doi: 10.1182/blood-2017-12-819870.