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      Patrolling monocytes scavenge endothelial-adherent sickle RBCs: a novel mechanism of inhibition of vaso-occlusion in SCD

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          Key Points

          • PMos scavenge endothelial adherent sickle RBCs in vitro and in vivo.

          • Vaso-occlusion in sickle mice can be controlled through manipulation of PMo numbers.

          Abstract

          Painful vaso-occlusive crisis (VOC) is the most common complication of sickle cell disease (SCD). Increasing evidence suggests that vaso-occlusion is initiated by increased adherence of sickle red blood cells (RBCs) to the vascular endothelium. Thus, the mechanisms that remove endothelial-attached sickle RBCs from the microvasculature are expected to be critical for optimal blood flow and prevention of VOC in SCD. We hypothesized that patrolling monocytes (PMos), which protect against vascular damage by scavenging cellular debris, could remove endothelial-adherent sickle RBCs and ameliorate VOC in SCD. We detected RBC (GPA +)-engulfed material in circulating PMos of patients with SCD, and their frequency was further increased during acute crisis. RBC uptake by PMos was specific to endothelial-attached sickle, but not control, RBCs and occurred mostly through ICAM-1, CD11a, and CD18. Heme oxygenase 1 induction, by counteracting the cytotoxic effects of engulfed RBC breakdown products, increased PMo viability. In addition, transfusions, by lowering sickle RBC uptake, improved PMo survival. Selective depletion of PMos in Townes sickle mice exacerbated vascular stasis and tissue damage, whereas treatment with muramyl dipeptide (NOD2 ligand), which increases PMo mass, reduced stasis and SCD associated organ damage. Altogether, these data demonstrate a novel mechanism for removal of endothelial attached sickle RBCs mediated by PMos that can protect against VOC pathogenesis, further supporting PMos as a promising therapeutic target in SCD VOC.

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          Author and article information

          Journal
          Blood
          Blood
          bloodjournal
          blood
          Blood
          Blood
          American Society of Hematology (Washington, DC )
          0006-4971
          1528-0020
          15 August 2019
          10 May 2019
          15 August 2020
          : 134
          : 7
          : 579-590
          Affiliations
          [1 ]Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY;
          [2 ]Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA; and
          [3 ]Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY
          Article
          PMC6695561 PMC6695561 6695561 2019/BLD2019000172
          10.1182/blood.2019000172
          6695561
          31076443
          © 2019 by The American Society of Hematology
          Page count
          Pages: 12
          Funding
          Funded by: National Institutes of Health;
          Categories
          2
          16
          36
          103
          Plenary Paper
          Red Cells, Iron, and Erythropoiesis

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