The recent CANTOS trial showed that administration of an antibody targeting IL-1b reduced coronary events, supporting the concept of anti-inflammatory therapy as a way to reduce cardiovascular disease (CVD). However, due to a modest effect and an excess of infections this treatment has not been approved for CVD treatment. This suggests the need for new approaches and for targeting anti-inflammatory therapy to patients who need it most. Clonal hematopoiesis (CH), a highly prevalent condition in the elderly, arises from somatic mutations that endow a proliferative advantage to hematopoietic stem cells (HSCs). CH increases the risk of myocardial infarction and stroke independently of traditional risk factors and in mouse models increases macrophage (Mf) inflammation and atherosclerosis. This application will seek to elucidate mechanisms linking clonal hematopoiesis to accelerated atherosclerosis, focusing on one particular cause of CH involving a gain of function in the signaling molecule JAK2. Relative to other common genetic variants giving rise to CH, this particular variant JAK2V617F (JAK2VF) increases Jak/Stat signaling, occurs at a younger age and imparts a greater risk of premature coronary heart disease. Our recent studies have shown a key role of Mf inflammasome activation, IL- 1b secretion and Mf proliferation in promoting atherosclerosis in mice expressing Jak2VF. Il-1b antibody treatment reduced features of atherosclerotic plaque instability in a mouse model of Jak2VF CH. In human studies we showed that the myocardial infarction associated with JAK2VF is increased by a common loss of function genetic variant in LNK that normally acts to suppress JAK/STAT signaling. This proposal will use mouse models that authentically replicate the human genetic variants to elucidate the mechanisms and consequences of Jak2VF- mediated inflammasome activation in atherosclerosis and the potential modulation of these effects by Lnk. The overall hypothesis is that metabolic changes in Jak2VF Mfs lead to Aim2 inflammasome activation, Gasdermin D cleavage, IL-1 secretion, pryoptotic cell death and necrotic core formation in atherosclerotic lesions. Our studies may suggest that suggest that precise application of anti-IL-1? or anti-inflammasome therapy based on CH status and LNK genotype could substantially reduce cardiovascular risk.
Clonal hematopoiesis (CH) has recently emerged as an important new risk factor for cardiovascular disease. This application will seek to elucidate the underlying mechanisms linking CH, inflammation and atherosclerosis.
