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

Authors
  • Liu, Yunfeng1
  • Jing, Fangmiao1
  • Yi, Woelsung1
  • Mendelson, Avital1
  • Shi, Patricia1
  • Walsh, Ronald2
  • Friedman, David F.3
  • Minniti, Caterina4
  • Manwani, Deepa5
  • Chou, Stella T.3
  • Yazdanbakhsh, Karina1
  • 1 Laboratory of Complement Biology, New York Blood Center, New York, NY;
  • 2 Division of Pathology, Montefiore Medical Center, Bronx, NY;
  • 3 Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA; and
  • 4 Division of Hematology, Department of Medicine, and
  • 5 Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Apr 05, 2018
Volume
131
Issue
14
Pages
1600–1610
Identifiers
DOI: 10.1182/blood-2017-12-819870
PMID: 29437594
PMCID: PMC5887768
Source
PubMed Central
License
Unknown

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-1hi) vs 6% in healthy controls and demonstrated that HO-1hi expression was dependent on uptake of heme-exposed endothelium. SCD patients with a recent VOC episode had lower numbers of HO-1hi 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-1hi patrolling monocyte may predispose SCD patients to VOC. These data suggest that HO-1hi patrolling monocytes are key players in VOC pathophysiology and have potential as therapeutic targets for VOC.

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