title: Hematopoietic interferon regulatory factor 8-deficiency accelerates atherosclerosis in mice.
abstract: OBJECTIVE
  Inflammatory leukocyte accumulation drives atherosclerosis. Although monocytes/macrophages and polymorphonuclear neutrophilic leukocytes (PMN) contribute to lesion formation, sequelae of myeloproliferative disease remain to be elucidated.
  
  
  RESULTS
  We used mice deficient in interferon regulatory factor 8 (IRF8(-/-)) in hematopoietic cells that develop a chronic myelogenous leukemia-like phenotype. Apolipoprotein E-deficient mice reconstituted with IRF8(-/-) or IRF8(-/-) apolipoprotein E-deficient bone marrow displayed an exacerbated atherosclerotic lesion formation compared with controls. The chronic myelogenous leukemia-like phenotype in mice with IRF8(-/-) bone marrow, reflected by an expansion of PMN in the circulation, was associated with an increased lesional accumulation and apoptosis of PMN, and enlarged necrotic cores. IRF8(-/-) compared with IRF8(+/+) PMN displayed unaffected reactive oxygen species formation and discharge of PMN granule components. In contrast, accumulating in equal numbers at sites of inflammation, IRF8(-/-) macrophages were defective in efferocytosis, lipid uptake, and interleukin-10 cytokine production. Importantly, depletion of PMN in low-density lipoprotein receptor or apolipoprotein E-deficient mice with IRF8(-/-) or IRF8(-/-) apolipoprotein E-deficient bone marrow abrogated increased lesion formation.
  
  
  CONCLUSIONS
  These findings indicate that a chronic myelogenous leukemia-like phenotype contributes to accelerated atherosclerosis in mice. Among proatherosclerotic effects of other cell types, this, in part, is linked to an expansion of functionally intact PMN.
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Döring
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.forename: Maik
authors.initials: M
authors.lastname: Drechsler
authors.forename: Erdenechimeg
authors.initials: E
authors.lastname: Shagdarsuren
authors.forename: Sweena M
authors.initials: SM
authors.lastname: Chaudhari
authors.forename: Svenja
authors.initials: S
authors.lastname: Meiler
authors.forename: Helene
authors.initials: H
authors.lastname: Hartwig
authors.forename: Mihail
authors.initials: M
authors.lastname: Hristov
authors.forename: Rory R
authors.initials: RR
authors.lastname: Koenen
authors.forename: Thomas
authors.initials: T
authors.lastname: Hieronymus
authors.forename: Martin
authors.initials: M
authors.lastname: Zenke
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology*; D016026:Bone Marrow Transplantation; D002199:Capillary Permeability; D005260:Female; D050835:Interferon Regulatory Factors / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology; D009195:Peroxidase / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011973:Receptors, LDL / Q000502:physiology; D000099185:Interferon Regulatory Factor-8
chemical_list: D001057:Apolipoproteins E; D050835:Interferon Regulatory Factors; D016753:Interleukin-10; D009195:Peroxidase; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; D000099185:Interferon Regulatory Factor-8