Distinct pro-inflammatory properties of myeloid cell-derived apolipoprotein E2 and E4 in atherosclerosis promotion
| Autor: | Emily Igel, Patrick R. Wolfkiel, Anja Jaeschke, David Y. Hui, April Haller, Melissa A. Orr-Asman |
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| Rok vydání: | 2021 |
| Předmět: |
Apolipoprotein E
Male Myeloid Apolipoprotein E2 Apolipoprotein E4 Apolipoprotein E3 Biochemistry Mice oxidative stress Myeloid Cells HSC hematopoietic stem cells ApoE apolipoprotein E Chemistry Inflammasome bone marrow transplant TNFα tumor necrosis factor α medicine.anatomical_structure Tumor necrosis factor alpha lipids (amino acids peptides and proteins) Female Myelopoiesis medicine.symptom medicine.drug Signal Transduction Research Article LDL low-density lipoproteins Lipoproteins Inflammation Mice Transgenic Proinflammatory cytokine Gene product NLRP3 NOD- LRR- and pyrin domain-containing protein 3 Apolipoproteins E inflammasome medicine Animals Humans oxLDL oxidized LDL Molecular Biology ApoE polymorphism HDL high-density lipoproteins Cell Biology Atherosclerosis IL interleukin Mice Inbred C57BL Cancer research LPS lipopolysaccharides BSA bovine serum albumin cholesterol efflux |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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