English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background: LNK/SH2B3 inhibits Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by hematopoietic cytokine receptors. Genome-wide association studies have shown association of a common single nucleotide polymorphism inLNK (R262W, T allele) with neutrophilia, thrombocytosis, and coronary artery disease. We have shown thatLNK(TT ) reduces LNK function and that LNK-deficient mice display prominent platelet–neutrophil aggregates, accelerated atherosclerosis, and thrombosis. Platelet–neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of NETs in atherosclerosis and thrombosis in mice with hematopoieticLnk deficiency.Methods: We bred mice with combined deficiency ofLnk and the NETosis-essential enzyme PAD4 (peptidyl arginine deiminase 4) and transplanted their bone marrow intoLdlr–/– mice. We evaluated the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK2V617F ).Results: Lnk -deficient mice displayed accelerated carotid artery thrombosis with prominent NETosis that was completely reversed by PAD4 deficiency. Thrombin-activatedLnk–/– platelets promoted increased NETosis when incubated withLnk–/– neutrophils compared with wild-type platelets or wild-type neutrophils. This involved increased surface exposure and release of oxidized phospholipids (OxPL) fromLnk–/– platelets, as well as increased priming and response ofLnk–/– neutrophils to OxPL. To counteract the effects of OxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06-scFv). E06-scFv reversed accelerated NETosis, atherosclerosis, and thrombosis inLnk–/– mice. We also showed increased NETosis when human induced pluripotent stem cell–derivedLNK(TT ) neutrophils were incubated withLNK(TT ) platelet/megakaryocytes, but not in isogenicLNK(CC ) controls, confirming human relevance. Using data from the UK Biobank, we found that individuals with the JAK2VF mutation only showed increased risk of coronary artery disease when also carrying the LNK R262W allele. Mice with hematopoieticLnk+/– andJak2VF clonal hematopoiesis showed accelerated arterial thrombosis but not atherosclerosis compared withJak2VF Lnk+/+ controls.Conclusions: HematopoieticLnk deficiency promotes NETosis and arterial thrombosis in an OxPL-dependent fashion. LNK(R262W) reduces LNK function in human platelets and neutrophils, promoting NETosis, and increases coronary artery disease risk in humans carryingJak2VF mutations. Therapies targeting OxPL may be beneficial for coronary artery disease in genetically defined human populations.

Oxidized Phospholipids Promote NETosis and Arterial Thrombosis in LNK(SH2B3) Deficiency