Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology

Abstract

Sickle cell disease (SCD) is a severe genetic blood disorder characterized by hemolytic anemia, episodic vaso-occlusion, and progressive organ damage. Current management of the disease remains symptomatic or preventative. Specific treatment targeting major complications such as vaso-occlusion is still lacking. Recent studies have identified various cellular and molecular factors that contribute to the pathophysiology of SCD. Here, we review the role of these elements and discuss the opportunities for therapeutic intervention.

Association of circulating transcriptomic profiles with mortality in sickle cell disease

“…Furthermore, pathway-based analysis of these transcriptomes clusters to signaling cascades known to be pathophysiologically relevant in SCD. 7,11,15,19,26,[33][34][35][36] Our data suggest that the transcriptome classifier is a biomarker that reflects disease severity as evidenced by abnormalities in important pathways that are driven by HbS polymerization and reflect the systemic nature of the complications of SCD. As such, FAIME analyses provide insights into the potential mechanistic and pathophysiological relevance of molecular clusters downstream of the inciting HgS polymerization event in SCD.…”

“…Seemingly heterogeneous pathways in porphyrin metabolism, bile secretion, and complement and coagulation cascades along with VEGF signaling and immune-mediated processes have all been shown to be directly relevant to SCD. 7,11,15,19,26,[33][34][35][36] Recently, meta-analysis of 4 published datasets of differentially regulated molecular pathways related to SCD demonstrated near identical pathways to those that are associated with survival in the current work including porphyrin metabolism, complement and coagulation cascades, VEGF signaling, and immune-mediated processes. 15 Another group evaluated differentially regulated genes by both RNAsequencing and conventional gene expression profiling in whole For personal use only.…”

ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease

“…35 Our studies demonstrate that oral administration of a single dose of both hydroxyurea and ARQ 092 efficiently inhibits neutrophil-endothelial cell and neutrophilplatelet interactions in cremaster venules and reduces neutrophil recruitment into the alveoli of TNF-α-challenged SCD mice. Interestingly, survival was improved by hydroxyurea alone or both hydroxyurea and ARQ 092, but not ARQ 092 alone.…”

“…35 Our study shows that ARQ 092 reduces the ligand-binding function of αMb2 integrin in stimulated neutrophils isolated from SCD patients. Importantly, we found that ARQ 092 inhibits αMb2 integrin function in neutrophils isolated from SCD mice after oral administration of the inhibitor.…”

“…35,42 In particular, preclinical and clinical studies with rivipansel (GMI-1070, a pan-selectin inhibitor) revealed that inhibition of leukocyte-endothelial cell interactions attenuates vaso-occlusion and improves survival in SCD mice, 29 and reduces time to resolution of vaso-occlusive events and requirement for opioid analgesia in SCD patients. 43 Nevertheless, complete inhibition of leukocyte-endothelial cell interactions could cause side effects by disrupting immune responses.…”