TY - JOUR
T1 - Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in JAK2V617F mice
AU - Wang, Wei
AU - Liu, Wenli
AU - Fidler, Trevor
AU - Wang, Ying
AU - Tang, Yang
AU - Woods, Brittany
AU - Welch, Carrie
AU - Cai, Bishuang
AU - Silvestre-Roig, Carlos
AU - Ai, Ding
AU - Yang, Yong Guang
AU - Hidalgo, Andres
AU - Soehnlein, Oliver
AU - Tabas, Ira
AU - Levine, Ross L.
AU - Tall, Alan R.
AU - Wang, Nan
N1 - Publisher Copyright:
© 2018 American Heart Association, Inc.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Erythrocytes
KW - Inflammasomes
KW - Inflammation
KW - Macrophages
UR - http://www.scopus.com/inward/record.url?scp=85058923019&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.118.313283
DO - 10.1161/CIRCRESAHA.118.313283
M3 - Article
C2 - 30571460
AN - SCOPUS:85058923019
SN - 0009-7330
VL - 123
SP - E35-E47
JO - Circulation Research
JF - Circulation Research
IS - 11
ER -