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Innate immune cells, major protagonists of sickle cell disease pathophysiology
Slimane Allali,1,2,3 Thiago Trovati Maciel,2,3 Olivier Hermine2,3,4 and Mariane de Montalembert1,3
1Department of General Pediatrics and Pediatric Infectious Diseases, Reference Center for Sickle Cell Disease, Necker Hospital for Sick Children, Assistance Publique – Hôpitaux de Paris (AP-HP), Paris Descartes University, Paris; 2Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris Descartes – Sorbonne Paris Cite University, Imagine Institute, Inserm U1163, Paris; 3Laboratory of Excellence GR-Ex, Paris and 4Department of Hematology, Necker Hospital for Sick Children, AP-HP, Paris Descartes University, Paris, France
ABSTRACT
Sickle cell disease (SCD), considered the most common monogenic dis- ease worldwide, is a severe hemoglobin disorder. Although the genetic and molecular bases have long been characterized, the pathophysiolo- gy remains incompletely elucidated and therapeutic options are limited. It has been increasingly suggested that innate immune cells, including mono- cytes, neutrophils, invariant natural killer T cells, platelets and mast cells, have a role in promoting inflammation, adhesion and pain in SCD. Here we provide a thorough review of the involvement of these novel, major protag- onists in SCD pathophysiology, highlighting recent evidence for innovative therapeutic perspectives.
Introduction
Sickle cell disease (SCD) is a life-threatening genetic hemoglobin disorder, char- acterized by chronic hemolytic anemia, recurrent painful vaso-occlusive events and progressive multiple organ damage.1 It is a global health issue, affecting millions of people worldwide, and its incidence is expected to increase to 400,000 neonates born per year by 2050.2 The genetic and molecular bases are fully characterized: SCD originates from a single nucleotide mutation of the β-globin gene, leading to polymerization of the abnormal deoxygenated hemoglobin S (HbS), which results in obstruction of small vessels by sickle-shaped red blood cells (RBC). However, in the last two decades, the pathophysiology has been found to be much more com- plex than originally thought, involving many factors other than RBC. Innate immune cells include circulating cells, such as monocytes, dendritic cells, neu- trophils, eosinophils, basophils, natural killer (NK) cells, invariant natural killer T (iNKT) cells and platelets, along with tissue-resident macrophages and mast cells.
Here we review the evidence for a contribution of innate immune cells to the pathophysiology of SCD.
Monocytes
Monocytes have long been considered important in SCD pathophysiology. Monocytosis is common in SCD and is positively correlated with markers of hemolysis and negatively with hemoglobin level.3 The absolute monocyte count is lower in SCD children being treated with hydroxyurea than in those not receiving such treatment, which may reflect another positive effect of hydroxyurea in SCD.4 In vitro, the interaction of RBC from SCD patients with cultured human umbilical vein endothelial cells was responsible for enhanced cellular oxidant stress, resulting in a two-fold increase in transendothelial migration of human peripheral blood monocytes.5 More importantly, monocytes from SCD patients display an activated profile, with increased expression of CD11b on their surface and increased produc- tion of interleukin (IL)-1β and tumor necrosis factor (TNF)-α as compared with healthy control monocytes.6-8 Upregulation of CD1 molecules on monocytes has been described, reflecting the activated status of these cells.9 Mononuclear cells
Ferrata Storti Foundation
Haematologica 2020 Volume 105(2):273-283
Correspondence:
SLIMANE ALLALI
slimane.allali@aphp.fr
MARIANE DE MONTALEMBERT
mariane.demontal@nck.aphp.fr
Received: June 18, 2019. Accepted: September 26, 2019. Pre-published: January 9, 2020.
doi:10.3324/haematol.2019.229989
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/273
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