title: Targeting Mac-1-mediated leukocyte-RBC interactions uncouples the benefits for acute vaso-occlusion and chronic organ damage.
abstract: Vaso-occlusive crisis (VOC) is one of the most common complications of sickle cell disease (SCD). Recurrent episodes of VOC may cause irreversible organ damage and early mortality in patients with SCD. Emerging evidence suggests that VOC arises from a complex cascade that involves interactions among multiple blood and endothelial cells in the vasculature. Previous studies have identified αMβ2 integrin (Mac-1) as a critical molecule that mediates heterotypic interactions between red blood cells (RBCs) and adherent leukocytes and promotes VOC in SCD mice. Here, we show that RBC-leukocyte interactions are significantly diminished in Mac-1-deficient SCD mice, leading to an improvement of blood flow rates and prolonged survival time in a tumor necrosis factor-alpha and surgical-trauma-induced VOC model. Mac-1-deletion, however, was not sufficient to reduce SCD-related chronic organ damage. Our results thus suggest uncoupled mechanisms between acute VOC benefits and the long-term complications of SCD that should be considered in future clinical trials.
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Department of Medicine and Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Chen
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Department of Medicine and Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Jungshan
authors.initials: J
authors.lastname: Chang
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Department of Medicine and Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Dachuan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Department of Medicine and Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinho
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Department of Medicine and Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Jang
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Department of Medicine and Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: paul.frenette@einstein.yu.edu.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D002448:Cell Adhesion; D002450:Cell Communication; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D014652:Vascular Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D016177:Macrophage-1 Antigen