Advertisement

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

Alessandro Matte, Antonio Recchiuti, Enrica Federti, Bérengère Koehl, Thomas Mintz, Wassim El Nemer, Pierre-Louis Tharaux, Valentine Brousse, Immacolata Andolfo, Alessia Lamolinara, Olga Weinberg, Angela Siciliano, Paul C. Norris, Ian R. Riley, Achille Iolascon, Charles N. Serhan, Carlo Brugnara and Lucia De Franceschi

Key points

  • Defective pro-resolving response to acute vaso-occlusive events characterizes murine sickle cell disease.

  • Treatment with 17R-RvD1 reduces inflammation and vascular dysfunction in SCD mice.

Abstract

The endogenous lipid mediators Resolvins (Rv) 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 in humanized SCD mice altered pro-resolving events following hypoxia/reperfusion. We demonstrate novel protective actions of 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: (i) enhancement of SCD erythrocytes and polymorphonuclear-leukocyte efferocytosis; (ii) blunting of NF-κB activation and (iii) reduction in inflammatory cytokines, vascular activation markers and E-selectin expression. Thus, 17R-RvD1 could represent a possible new therapeutic strategy for the inflammatory vasculopathy of SCD.

  • Submitted July 31, 2018.
  • Accepted October 23, 2018.