Resolution of sickle cell disease–associated inflammation and tissue damage with 17R-resolvin D1

Author:

Matte Alessandro1,Recchiuti Antonio2ORCID,Federti Enrica1,Koehl Bérengère3,Mintz Thomas4,El Nemer Wassim3,Tharaux Pierre-Louis4ORCID,Brousse Valentine5,Andolfo Immacolata6ORCID,Lamolinara Alessia7,Weinberg Olga8,Siciliano Angela1,Norris Paul C.9ORCID,Riley Ian R.9,Iolascon Achille6ORCID,Serhan Charles N.9ORCID,Brugnara Carlo10,De Franceschi Lucia1ORCID

Affiliation:

1. Department of Medicine, University of Verona, Policlinico GB Rossi–Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy;

2. Department of Medical, Oral, and Biotechnology Science and Center of Excellence on Aging and Translational Medicine, “G. d’Annunzio” University of Chieti, Chieti, Italy;

3. Laboratoire d’Excellence GR-Ex, Unité Biologie Intégrée du Globule Rouge, NTS, INSERM, Paris Diderot University, Sorbonne Paris Cité University, Paris, France;

4. Paris Cardiovascular Research Centre, INSERM and Paris Descartes University, Paris, France;

5. Assistance Publique Hopitaux de Paris, Necker Hospital, Paris, France;

6. Department of Molecular Medicine and Medical Biotechnologies, Federico II University, and CEINGE, Biotecnologie Avanzate, Naples, Italy;

7. Center of Excellence on Aging and Translational Medicine, Department of Medicine and Aging Science, “G. D’Annunzio” University of Chieti, Chieti, Italy;

8. Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA;

9. Center of Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; and

10. Department of Laboratory Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA

Abstract

Abstract Resolvins (Rvs), endogenous lipid mediators, play a key role in the resolution of inflammation. Sickle cell disease (SCD), a genetic disorder of hemoglobin, is characterized by inflammatory and vaso-occlusive pathologies. We document altered proresolving events following hypoxia/reperfusion in humanized SCD mice. We demonstrate novel protective actions of 17R-resolvin D1 (17R-RvD1; 7S, 8R, 17R-trihydroxy-4Z, 9E, 11E, 13Z, 15E, 19Z-docosahexaenoic acid) in reducing ex vivo human SCD blood leukocyte recruitment by microvascular endothelial cells and in vivo neutrophil adhesion and transmigration. In SCD mice exposed to hypoxia/reoxygenation, oral administration of 17R-RvD1 reduces systemic/local inflammation and vascular dysfunction in lung and kidney. The mechanism of action of 17R-RvD1 involves (1) enhancement of SCD erythrocytes and polymorphonuclear leukocyte efferocytosis, (2) blunting of NF-κB activation, and (3) a reduction in inflammatory cytokines, vascular activation markers, and E-selectin expression. Thus, 17R-RvD1 might represent a new therapeutic strategy for the inflammatory vasculopathy of SCD.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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