Increased eosinophil counts are associated with
cardiovascular disease and may be an independent predictor of major cardiovascular events. However, the causality and underlying mechanisms are poorly understood. Genome-wide association studies have shown an association of a common LNK variant (R262W, T allele) with
eosinophilia and atherothrombotic disorders. LNK(TT) reduces LNK function, and Lnk-deficient mice display accelerated
atherosclerosis and
thrombosis. This study was undertaken to assess the role of eosinophils in arterial
thrombosis in mice with hematopoietic Lnk deficiency. Hematopoietic Lnk deficiency increased circulating and activated eosinophils, JAK/STAT signaling in eosinophils, and carotid arterial
thrombosis with increased eosinophil abundance and extracellular trap formation (EETosis) in thrombi. Depletion of eosinophils by anti-
Siglec-F antibody or by the ΔdbIGata1 mutation eliminated eosinophils in thrombi and markedly reduced
thrombosis in mice with hematopoietic Lnk deficiency but not in control mice. Eosinophil depletion reduced neutrophil abundance and NETosis in thrombi without altering circulating neutrophil counts. To assess the role of Lnk specifically in eosinophils, we crossed Lnkf/f mice with eoCre mice. LnkΔeos mice displayed isolated
eosinophilia, increased eosinophil activation, and accelerated arterial
thrombosis associated with increased EETosis and NETosis in thrombi.
DNase I infusion abolished EETs and neutrophil extracellular traps (NETs) in thrombi and reversed the accelerated
thrombosis. Human induced pluripotent stem cell-derived LNK(TT) eosinophils showed increased activation and EETosis relative to isogenic LNK(CC) eosinophils, demonstrating human relevance. These studies show a direct link between
eosinophilia, EETosis, and
atherothrombosis in hematopoietic Lnk deficiency and an essential role of eosinophil LNK in suppression of arterial
thrombosis.