Platelet TLR9 Promotes Pulmonary Thrombo-Inflammation in Sickle Cell Disease

Sickle cell disease (SCD) is a monogenic disorder, which affects millions of people worldwide. Erythrocyte sickling, chronic hemolysis and ischemia-reperfusion injury promote sterile inflammation in SCD.Recent evidence suggests that activation of innate immune pathways in platelets contribute to development of acute chest syndrome (ACS), a type of acute lung injury in SCD by promoting occlusion of lung arterioles by neutrophil-platelet-erythrocyte aggregates (pulmonary thrombo-inflammation). Although, TLR9 is functionally expressed on the surface of activated platelets and may bind to circulating double stranded DNA, the role of platelet TLR-9 in promoting pulmonary thrombo-inflammation in SCD remains elusive. Our initial findings using intravenous lipopolysaccharide (0.1 μg/kg LPS) or oxy-hemoglobin (10 μmole/kg oxy-Hb) triggered model of vaso-occlusive crisis in transgenic-humanized SCD mice reveal that pulmonary vaso-occlusion is associated with elevated surface-expression of platelet TLR-9 in SCD mice. Unlike SCD mice, surface-expression of TLR9 was undetectable in the platelets of control mice challenged with either IV LPS or oxy-Hb. These findings suggest a potential role for platelet TLR9 in promoting lung vaso-occlusion and injury in SCD. Currently, studies are in progress to identify the innate immune signaling downstream to platelet TLR9, contributing to pulmonary thrombo-inflammation in SCD.

Sundd:IHP Therapeutics: Research Funding; Bayer Hemophilia Award Program: Research Funding; Novartis corporation: Research Funding; CSL Behring Inc: Research Funding.