Impaired pro-resolving mechanisms promote abnormal NETosis, fueling autoimmunity in sickle cell disease

Sickle cell disease (SCD) is a hereditary disorder of red blood cells that is recognized for its global prevalence and significant associated mortality and morbidity. The pathophysiology of SCD is characterized by anemia, chronic hemolysis, and vaso-occlusive crises. Overactive neutrophils in individuals with SCD can generate neutrophil extracellular traps (NETs), contributing to vascular injury and elevating the risk of infections. However, the precise role of NETs in SCD and their relationship with an imbalanced immune response remains inadequately understood. In this investigation, we analyzed a cohort of 23 volunteers diagnosed with SCD, highlighting an increase in inflammatory markers and autoantibodies. Our findings indicated a higher prevalence of NET-forming neutrophils at baseline and following ex vivo activation when compared to healthy controls. Furthermore, we identified a diminished expression of receptors for specialized pro-resolving lipid mediators (SPMs), specifically ALX, GPR32/DRV1, and GPR18/DRV2, which are known to play protective roles in the pathophysiology of SCD. The ex vivo supplementation with SPMs RvD1 and RvD4 yielded a significant reduction in NET formation by neutrophils. This intervention also facilitated the clearance of NETs by macrophages and enhanced neutrophil phagocytic activity against bacteria. In summary, these results indicate that a compromised pro-resolving capability in SCD can adversely influence the equilibrium between NETosis and their active clearance, potentially fostering the production of autoantibodies. The administration of exogenous resolvins decreased NET formation while enhancing their active clearance and restoring neutrophil antimicrobial functions. Thus, the findings presented herein emphasize the critical role of SPMs in reprogramming host responses in SCD, with implications for limiting disease progression as well as reducing the risks of infections and sepsis.