The role of eosinophil in thrombosis and atherosclerosis in LNK deficiency

Project Summary/Abstract Atherothrombotic cardiovascular disease (ACD) remains the major cause of morbidity and mortality in the US. Increased number and activation of neutrophils and eosinophils are associated with increased risk of ACD. The underlying mechanisms of these associations are incompletely understood, and no therapies specifically address these risk factors. Human GWAS have unraveled association of a common polymorphism of LNK/SH2B3 (T allele, R262W) with an increased risk of ACD and increased neutrophil, platelet and eosinophil counts. This LNK variant is carried by ~75% European, ~50% Latin American and ~30% African American populations. We have shown that LNK(R262W) reduces LNK function and LNK deficiency in blood cells promotes atherosclerosis in mouse models. More recently, we have shown that enhanced neutrophil extracellular trap formation promotes atherothrombosis in Lnk-/- mice. Mechanistically, activated LNK deficient platelets present increased oxidized phospholipids, priming neutrophils for NETosis. While eosinophils represent a small fraction of white blood cells, there is accumulating evidence that they play an important role in thrombosis and atherosclerosis. We have preliminary data showing prominent eosinophilia and reversal of accelerated thrombosis in Lnk-/- mice by antibody mediated eosinophil depletion. The preliminary data suggests a major role of eosinophils in eosinophil, neutrophil and platelet interactions that promotes thrombosis in hematopoietic Lnk-/- mice. The broad goal of this project is to investigate mechanisms connecting LNK deficiency to atherosclerosis and thrombosis. A major new hypothesis is that hematopoietic LNK deficiency promotes arterial thrombosis, plaque erosion and atherosclerosis at least in part via increased eosinophil production, eosinophil activation and interaction with platelets and neutrophils. In this proposal, we will follow the leads and generate novel mouse models including a mouse line with floxed Lnk to explore the mechanisms underlying the role of eosinophils in atherosclerosis and atherothrombosis in hematopoietic LNK deficiency. A better understanding of these mechanisms may lead to development of new therapeutic approaches to managing ACD risks, probably in populations with defined genetic background, e.g. LNK(R262W) polymorphism.