Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in JAK2V617F mice

Wei Wang, Wenli Liu, Trevor Fidler, Ying Wang, Yang Tang, Brittany Woods, Carrie Welch, Bishuang Cai, Carlos Silvestre-Roig, Ding Ai, Yong Guang Yang, Andres Hidalgo, Oliver Soehnlein, Ira Tabas, Ross L. Levine, Alan R. Tall, Nan Wang

Research output: Contribution to journalArticlepeer-review

167 Scopus citations


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 erythrophagocytosis. Jak2VF erythrocytes were more susceptible to phagocytosis by wild-type macrophages and showed decreased surface expression of CD47, a “don'teat-me” signal. Human JAK2VF erythrocytes were also more susceptible to erythrophagocytosis. Jak2VF 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 Jak2VF expression promotes early lesion formation and increased complexity in advanced atherosclerosis. In addition to increasing hematopoiesis and neutrophil infiltration in early lesions, Jak2VF 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.

Original languageEnglish
Pages (from-to)E35-E47
JournalCirculation Research
Issue number11
StatePublished - 2018
Externally publishedYes


  • Atherosclerosis
  • Erythrocytes
  • Inflammasomes
  • Inflammation
  • Macrophages


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