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.

METHODS AND 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: Yvonne Döring, Oliver Soehnlein, Maik Drechsler, Erdenechimeg Shagdarsuren, Sweena M Chaudhari, Svenja Meiler, Helene Hartwig, Mihail Hristov, Rory R Koenen, Thomas Hieronymus, Martin Zenke, Christian Weber, Alma Zernecke
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 7 Pg. 1613-23 (Jul 2012) ISSN: 1524-4636 [Electronic] United States
• PMID: 22556330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Interferon Regulatory Factors
• Reactive Oxygen Species
• Receptors, LDL
• interferon regulatory factor-8
• Interleukin-10
• Peroxidase

Topics

• Animals
• Apolipoproteins E (physiology)
• Apoptosis
• Atherosclerosis (etiology)
• Bone Marrow Transplantation
• Capillary Permeability
• Female
• Interferon Regulatory Factors (physiology)
• Interleukin-10 (biosynthesis)
• Macrophages (physiology)
• Mice
• Mice, Inbred C57BL
• Neutrophils (physiology)
• Peroxidase (physiology)
• Reactive Oxygen Species (metabolism)
• Receptors, LDL (physiology)