- Bérengère Koehl1,
- Pierre Nivoit2,
- Wassim El Nemer1,
- Olivia Lenoir2,
- Patricia Hermand1,
- Catia Pereira1,
- Valentine Brousse3,
- Léa Guyonnet4,
- Giulia Ghinatti5,
- Malika Benkerrou6,
- Yves Colin1,
- Caroline Le Van Kim1 and
- Pierre-Louis Tharaux2,*
- 1 Inserm/University Sorbonne Paris Cite'-Paris Diderot/INTS, Paris, France;
- 2 Inserm/University Sorbonne Paris Cite'-Paris Descartes/PARCC, Paris, France;
- 3 Assistance Publique Hopitaux de Paris, Necker Hospital, Paris, France;
- 4 Inserm/University Sorbonne Paris Cite', Paris Descartes/PARCC/Luxembourg Institute of Health;
- 5 Inserm/University Sorbonne Paris Cite', Paris Descartes/PARCC, Paris, France;
- 6 Assistance Publique Hopitaux de Paris, Robert Debre' Hospital, Reference Centre of Sickle Cell Disea
- ↵* Corresponding author; email:
Although the primary origin of sickle cell disease is a hemoglobin disorder, several cell types contribute considerably to the physiopathology of the disease. The adhesion of neutrophils to activated endothelium is critical in sickle cell disease pathophysiology and the targeting of neutrophils and their interactions with endothelium represent important opportunities for new therapeutics. We focused on endothelin-1, a mediator involved in neutrophil activation and recruitment in tissues, and we investigated the involvement of the endothelin receptors in 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 mouse model and patients indicate that blocking endothelin receptors, particularly ETB receptor highly influences neutrophils recruitment under inflammatory conditions in sickle cell disease. We show that human neutrophils display functional ETB receptors with calcium signaling capability leading to increased adhesion to the endothelium, through action on both endothelial cells and neutrophils. ETB intact function was also found to be required for TNFα-dependent upregulation of CD11b on neutrophils. Furthermore, we confirmed that human neutrophils synthesize endothelin-1 that may be involved in autocrine and paracrine pathophysiological actions. Thus, the endothelin-ETB axis should be considered as a cytokine-like potent pro-inflammatory pathway in sickle cell disease. Blockade of endothelin receptor, including ETB, may provide major benefits for preventing or treating vaso-occlusive crises of sickle cell patients.
- Received September 19, 2016.
- Accepted March 30, 2017.
- Copyright © 2017, Ferrata Storti Foundation