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Wang, Wei; Liu, Wenli; Fidler, Trevor; Wang, Ying; Tang, Yang; Woods, Brittany; Welch, Carrie; Cai, Bishuang; Silvestre-Roig, Carlos; Ai, Ding; Yang, Yong-Guang; Hidalgo, Andres; Söhnlein, Oliver; Tabas, Ira; Levine, Ross L.; Tall, Alan R.; Wang, Nan (2018): Macrophage Inflammation, Erythrophagocytosis, and Accelerated Atherosclerosis in Jak2(V617F) Mice. In: Circulation Research, Vol. 123, No. 11, E35-E47
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Abstract

Rationale: The mechanisms driving atherothrombotic risk in individuals with JAK2(V617F) (Jak2(VF)) 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 Jak2(VF) expression. Methods and Results: Irradiated low-density lipoprotein receptor knockout (Ldlr(-/-)) mice were transplanted with bone marrow from wild-type or Jak2(VF) mice and fed a high-fat high-cholesterol Western diet. Hematopoietic functions and atherosclerosis were characterized. After 7 weeks of Western diet, Jak2(VF) mice showed increased atherosclerosis. Early atherosclerotic lesions showed increased neutrophil adhesion and content, correlating with lesion size. After 12 weeks of Western diet, Jak2(VF) lesions showed increased complexity, with larger necrotic cores, defective efferocytosis, prominent iron deposition, and costaining of erythrocytes and macrophages, suggesting erythrophagocytosis. Jak2(VF) erythrocytes were more susceptible to phagocytosis by wild-type macrophages and showed decreased surface expression of CD47, a "don't-eat-me" signal. Human JAK2VF erythrocytes were also more susceptible to erythrophagocytosis. Jak2(VF) macrophages displayed increased expression and production of proinflammatory cytokines and chemokines, prominent inflammasome activation, increased p38 MAPK (mitogen-activated protein kinase) signaling, and reduced levels of MerTK (c-Mer tyrosine kinase), a key molecule mediating efferocytosis. Increased erythrophagocytosis also suppressed efferocytosis. Conclusions: Hematopoietic Jak2(VF) expression promotes early lesion formation and increased complexity in advanced atherosclerosis. In addition to increasing hematopoiesis and neutrophil infiltration in early lesions, Jak2(VF) caused cellular defects in erythrocytes and macrophages, leading to increased erythrophagocytosis but defective efferocytosis. These changes promote accumulation of iron in plaques and increased necrotic core formation which, together with exacerbated proinflammatory responses, likely contribute to plaque instability.