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

Yunfeng Liu, Hui Zhong, Weili Bao, Avital Mendelson, Xiuli An, Patricia Shi, Stella T. Chou, Deepa Manwani and Karina Yazdanbakhsh

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 (RBC) 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 (PMo) 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 PMo was specific to endothelialattached sickle, but not control RBCs and occurred mostly through ICAM-1, CD11a and CD18. HO-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 PMo 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 PMo that can protect against VOC pathogenesis, further supporting PMo as a promising therapeutic target in SCD VOC.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 (RBC) 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 (PMo) 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 PMo was specific to endothelialattached sickle, but not control RBCs and occurred mostly through ICAM-1, CD11a and CD18. HO-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 PMo 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 PMo that can protect against VOC pathogenesis, further supporting PMo as a promising therapeutic target in SCD VOC.

  • Submitted February 14, 2019.
  • Revision received May 2, 2019.
  • Accepted May 2, 2019.