Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2(V617F) mice Journal Article

Authors: Wang, W.; Liu, W.; Fidler, T.; Wang, Y.; Tang, Y.; Woods, B.; Welch, C.; Cai, B.; Silvestre-Roig, C.; Ai, D.; Yang, Y. G.; Hidalgo, A.; Soehnlein, O.; Tabas, I.; Levine, R. L.; Tall, A. R.; Wang, N.
Article Title: Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2(V617F) mice
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.
Keywords: inflammation; atherosclerosis; macrophages; erythrocytes; inflammasomes
Journal Title: Circulation Research
Volume: 123
Issue: 11
ISSN: 0009-7330
Publisher: Lippincott Williams & Wilkins  
Date Published: 2018-11-09
Start Page: e35
End Page: e47
Language: English
DOI: 10.1161/circresaha.118.313283
PUBMED: 30571460
PROVIDER: scopus
PMCID: PMC6309796
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
Citation Impact
MSK Authors
  1. Ross Levine
    614 Levine
  2. Brittany Anne Woods
    11 Woods