Soluble LIGHT (TNFSF14) activates endothelial cells, thereby priming the first vessel-occlusive events in acute sickle cell disease

In sickle cell disease (SCD), the red blood cells carry a mutated form of hemoglobin (HbS) leading to altered shape and deformability. The mutation causes abnormal hemorheological properties, mechanical hemolysis, and adhesion. The chronic vascular inflammation observed in SCD and hemolysis-related endothelium activation may trigger the vaso-occlusion of blood vessels. The prothrombotic and pro-inflammatory LIGHT/TNFSF14 is a tumor necrosis factor (TNF)- superfamily cytokine implicated in various inflammatory diseases. It is expressed by various immune cells and is considered an actor in T cell-mediated immunity and immune cell recruitment. LIGHT has also been shown to activate endothelial cells (ECs) strongly. LIGHT levels are high in the plasma of SCD patients, and platelets are a major source of its circulating form. We studied a cohort of 82 homozygous adult patients with SCD ( n =108 samples) to determine whether LIGHT levels were linked to the clinical state of patients included in the ‘ Basal ’ steady state or during an ‘ Acute ’ crisis. Soluble LIGHT levels were high in the plasma of SCD patients during acute phases of the disease, particularly during painful occlusive crises. LIGHT levels were associated with Hb levels and inflammatory markers (mainly interferon-γ and tumor necrosis factor-α, specifically in acute SCD patients). Our findings confirm that LIGHT is a strong activator of cultured ECs, inducing a type II inflammatory cytokine profile and the expression of adhesion molecules. Using a physiological flow adhesion test on biochips, we showed that the LIGHT-induced activation of ECs led to the adhesion of both sickle platelets (but not their AA counterparts), and in a less extend sickle RBCs to activated HUVECs, potentially constituting the first step in vaso-occlusion. Indeed, the pretreatment of HUVECs with neutralizing polyclonal Abs against LIGHT, but not the non-specific counterpart, showed a reversal of both the inflammation process activated by LIGHT treatment and platelet adhesion to endothelial cells. Soluble LIGHT appears to be a promising therapeutic target for preventing adverse occlusive events in SCD through the blockade of its receptor, to prevent the adhesion of blood cell components to the endothelium. Future studies should consider whether soluble LIGHT contributes to other clinical complications in SCD. HIGHLIGHTS ### Competing Interest Statement Pr Pablo Bartolucci declares being member on a standing advisory council or committee consultancy for Roche, Addmedica, Bluebird bio, Emmaus, Agios, Global Blood Therapeutics, Novartis and Hemanext Inc. PB declares being co‐founder of Innovhem. The other authors have no competing financial interests to declare. * TNFSF14 : tumor necrosis factor superfamily member 14 HUVECs : human umbilical vein endothelial cells SCD : sickle-cell disease RBCs : red blood cells ECs : endothelial cells ICAM-1 : intercellular adhesion molecule-1 VCAM-1 : vascular cell adhesion molecule-1 vWF : von willebrand factor VOC : vaso-occlusive crisis ACS : acute chest syndrome DHTR : delayed hemolytic transfusion reaction LDH : lactate dehydrogenase Hb : hemoglobin Hct : hematocrit sPLA2 : secreted phospholipase A2.