Macrophage Inflammation, Erythrophagocytosis, and Accelerated Atherosclerosis in Jak2V617F Mice

Rationale: The mechanisms driving atherothrombotic risk in individuals with JAK2V617F (Jak2VF) positive clonal hematopoiesis or myeloproliferative neoplasms are poorly understood. Objective: The goal of this study was to assess atherosclerosis and underlying mechanisms in hypercholesterolemic mice with hematopoietic Jak2VF expression. Methods and Results: Irradiated low-density lipoprotein receptor knockout (Ldlr−/−) mice were transplanted with bone marrow from wild-type or Jak2VF mice and fed a high-fat high-cholesterol Western diet. Hematopoietic functions and atherosclerosis were characterized. After 7 weeks of Western diet, Jak2VF mice showed increased atherosclerosis. Early atherosclerotic lesions showed increased neutrophil adhesion and content, correlating with lesion size. After 12 weeks of Western diet, Jak2VF lesions showed increased complexity, with larger necrotic cores, defective efferocytosis, prominent iron deposition, and costaining of erythrocytes and macrophages, suggesting erythrophagoc...