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Distinct pro-inflammatory properties of myeloid cell-derived apolipoprotein E2 and E4 in atherosclerosis promotion.

Authors
  • Igel, Emily1
  • Haller, April1
  • Wolfkiel, Patrick R1
  • Orr-Asman, Melissa1
  • Jaeschke, Anja1
  • Hui, David Y2
  • 1 Department of Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • 2 Department of Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. Electronic address: [email protected]
Type
Published Article
Journal
Journal of Biological Chemistry
Publisher
American Society for Biochemistry and Molecular Biology
Publication Date
Aug 21, 2021
Volume
297
Issue
3
Pages
101106–101106
Identifiers
DOI: 10.1016/j.jbc.2021.101106
PMID: 34425108
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Polymorphisms in the apolipoprotein E (apoE) gene are risk factors for chronic inflammatory diseases including atherosclerosis. The gene product apoE is synthesized in many cell types and has both lipid transport-dependent and lipid transport-independent functions. Previous studies have shown that apoE expression in myeloid cells protects against atherogenesis in hypercholesterolemic ApoE-/- mice. However, the mechanism of this protection is still unclear. Using human APOE gene replacement mice as models, this study showed that apoE2 and apoE4 expressed endogenously in myeloid cells enhanced the inflammatory response via mechanisms independent of plasma lipoprotein transport. The data revealed that apoE2-expressing myeloid cells contained higher intracellular cholesterol levels because of impaired efflux, causing increasing inflammasome activation and myelopoiesis. In contrast, intracellular cholesterol levels were not elevated in apoE4-expressing myeloid cells, and its proinflammatory property was found to be independent of inflammasome signaling and related to enhanced oxidative stress. When ApoE-/- mice were reconstituted with bone marrow from various human APOE gene replacement mice, effective reduction of atherosclerosis was observed with marrow cells obtained from APOE3 but not APOE2 and APOE4 gene replacement mice. Taken together, these results documented that apoE2 and apoE4 expression in myeloid cells promotes inflammation via distinct mechanisms and promotes atherosclerosis in a plasma lipoprotein transport-independent manner. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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