The role of Ninjurin-1 deficiency in Jak2V617F clonal hematopoiesis mediated atherosclerosis plaque progression
Clonal haematopoiesis of indeterminate potential (CHIP) involves age-related acquisition and expansion of genes frequently mutated in haematologic malignancies (e.g. DNMT3A, TET2, or JAK2).  JAK2 heightens cardiovascular disease (CVD) risk. The mechanism, although incompletely understood, involves pyroptosis and plasma membrane rupture, mediated by Ninjurin-1 (NINJ1), followed by release of damage-associated molecular patterns and cytokines. Moreover, individuals with JAK2-CHIP have elevated levels of circulating interleukin-17 receptor-A (IL-17RA). IL-17RA signalling, implicated in autoimmunity, paradoxically may have a protective role in atherogenesis. IL-17A produced by T helper 17 (Th17) cells binding to IL-17RA in myeloid cells may induce a TREM2 macrophage response to create a feedback loop and dampen further inflammation. The proteomic association between JAK2-CHIP and IL-17RA, along with the potential role of IL-17RA signalling in atherosclerosis, led us to hypothesize that IL-17RA signalling modifies CVD risk among individuals with JAK2-CHIP.