title: The endothelin B receptor plays a crucial role in the adhesion of neutrophils to the endothelium in sickle cell disease.
abstract: Although the primary origin of sickle cell disease is a hemoglobin disorder, many types of cells contribute considerably to the pathophysiology of the disease. The adhesion of neutrophils to activated endothelium is critical in the pathophysiology of sickle cell disease and targeting neutrophils and their interactions with endothelium represents an important opportunity for the development of new therapeutics. We focused on endothelin-1, a mediator involved in neutrophil activation and recruitment in tissues, and investigated the involvement of the endothelin receptors in the interaction of neutrophils with endothelial cells. We used fluorescence intravital microscopy analyses of the microcirculation in sickle mice and quantitative microfluidic fluorescence microscopy of human blood. Both experiments on the mouse model and patients indicate that blocking endothelin receptors, particularly ETBreceptor, strongly influences neutrophil recruitment under inflammatory conditions in sickle cell disease. We show that human neutrophils have functional ETBreceptors with calcium signaling capability, leading to increased adhesion to the endothelium through effects on both endothelial cells and neutrophils. Intact ETBfunction was found to be required for tumor necrosis factor α-dependent upregulation of CD11b on neutrophils. Furthermore, we confirmed that human neutrophils synthesize endothelin-1, which may be involved in autocrine and paracrine pathophysiological actions. Thus, the endothelin-ETBaxis should be considered as a cytokine-like potent pro-inflammatory pathway in sickle cell disease. Blockade of endothelin receptors, including ETB, may provide major benefits for preventing or treating vaso-occlusive crises in sickle cell patients.
authors.affiliation: Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, France; Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Reference Centre of Sickle Cell Disease, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Koehl
authors.affiliation: Inserm Paris Cardiovascular Centre (PARCC), Université Sorbonne Paris Cité, Université Paris Descartes & Laboratoire d'Excellence GR-Ex, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Nivoit
authors.affiliation: Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, France.
authors.forename: Wassim
authors.initials: W
authors.lastname: El Nemer
authors.affiliation: Inserm Paris Cardiovascular Centre (PARCC), Université Sorbonne Paris Cité, Université Paris Descartes & Laboratoire d'Excellence GR-Ex, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Lenoir
authors.affiliation: Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hermand
authors.affiliation: Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, France; Assistance Publique-Hôpitaux de Paris, Necker Hospital, Reference Centre of Sickle Cell Disease, France.
authors.forename: Catia
authors.initials: C
authors.lastname: Pereira
authors.forename: Valentine
authors.initials: V
authors.lastname: Brousse
authors.affiliation: Inserm Paris Cardiovascular Centre (PARCC), Université Sorbonne Paris Cité, Université Paris Descartes & Laboratoire d'Excellence GR-Ex, France; Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg.
authors.forename: Léa
authors.initials: L
authors.lastname: Guyonnet
authors.affiliation: Inserm Paris Cardiovascular Centre (PARCC), Université Sorbonne Paris Cité, Université Paris Descartes & Laboratoire d'Excellence GR-Ex, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ghinatti
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Reference Centre of Sickle Cell Disease, France.
authors.forename: Malika
authors.initials: M
authors.lastname: Benkerrou
authors.affiliation: Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Colin
authors.affiliation: Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, France caroline.le-van-kim@inserm.fr pierre-louis.tharaux@inserm.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Van Kim
authors.affiliation: Inserm Paris Cardiovascular Centre (PARCC), Université Sorbonne Paris Cité, Université Paris Descartes & Laboratoire d'Excellence GR-Ex, France caroline.le-van-kim@inserm.fr pierre-louis.tharaux@inserm.fr.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
mesh_terms: D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007958:Leukocyte Count; D036904:Leukocyte Rolling; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D016177:Macrophage-1 Antigen; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium