HO-1hi patrolling monocytes protect against vaso-occlusion in sickle cell disease

Abstract

Patients with sickle cell disease (SCD) suffer from intravascular hemolysis associated with vascular injury and dysfunction in mouse models, and painful vaso-occlusive crisis (VOC) involving increased attachment of sickle erythrocytes and activated leukocytes to damaged vascular endothelium. Patrolling monocytes, which normally scavenge damaged cells and debris from the vasculature, express higher levels of anti-inflammatory heme oxygenase 1 (HO-1), a heme degrading enzyme. Here, we show that HO-1-expressing patrolling monocytes protect SCD vasculature from ongoing hemolytic insult and vaso-occlusion. We found that a mean 37% of patrolling monocytes from SCD patients express very high levels of HO-1 (HO-1) vs 6% in healthy controls and demonstrated that HO-1 expression was dependent on uptake of heme-exposed endothelium. SCD patients with a recent VOC episode had lower numbers of HO-1 patrolling monocytes. Heme-mediated vaso-occlusion by mouse SCD red blood cells was exacerbated in mice lacking patrolling monocytes, and reversed following transfer of patrolling monocytes. Altogether, these data indicate that SCD patrolling monocytes remove hemolysis-damaged endothelial cells, resulting in HO-1 upregulation and dampening of VOC, and that perturbation in patrolling monocyte numbers resulting in lower numbers of HO-1 patrolling monocyte may predispose SCD patients to VOC. These data suggest that HO-1 patrolling monocytes are key players in VOC pathophysiology and have potential as therapeutic targets for VOC.

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

“…A monocyte‐tumor necrosis factor‐endothelial activation axis has recently been described in animal models of SCD, with monocytes generating large amounts of pro‐inflammatory cytokines. A recent study also has shed light on the potential importance of non‐classical “patrolling” monocytes and vaso‐occlusion …”

How I safely transfuse patients with sickle-cell disease and manage delayed hemolytic transfusion reactions

“…Plasma exchange Because free heme and free Hb can have deleterious effects on vasculature, 10,11 plasma exchange may be effective in severe cases of hyperhemolysis 58 and was successfully shown to detoxify heme in patients with acute MOF without DHTR. 59 However, the extracorporeal volume, which can further lower the Hb level, needs to be considered.…”

“…Hyperhemolysis can induce multiorgan failure (MOF) and death, most likely because of damage to the underlying vasculature by released free hemoglobin (Hb) and heme. 10,11 Additional transfusions are frequently prescribed but can worsen hemolysis. Based on retrospective studies, the incidence of severe DHTR is 11.5% to 16% with only ABO and RhD matching and 4% to 7% in patients matched for Rh (D, C, E, c, e) and K (supplemental Table 1, available on the Blood Web site); in an adult cohort, DHTRs represented 4.2% of all causes of death in SCD.…”

Patrolling monocytes in sickle cell hemolytic conditions

“…We recently reported that a novel circulating PMo subset expressing very high levels of HO-1 (HO-1 hi ) is present exclusively in SCD patients and that patients with a recent VOC episode have reduced numbers of HO-1 hi PMo. 21 We showed that PMo clear hemolysisdamaged ECs with a concomitant upregulation of HO-1. ICAM-1 and PS expression on ECs was shown to be required for induction of HO-1 hi expression in PMo when cultured with hemolysis-damaged ECs.…”