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Cited by 46Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismLipoproteins and Cardiovascular Health

Loss of Macrophage Low-Density Lipoprotein Receptor–Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition

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Zhu, Lin, Giunzioni, Ilaria, Tavori, Hagai, Covarrubias, Roman, Ding, Lei, Zhang, Youmin, Ormseth, Michelle, Major, Amy S. +3 more·2016·Arteriosclerosis, Thrombosis, and Vascular Biology
DOI 10.1161/atvbaha.116.307736PMC PMC5346022
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Abstract

Objective—: Antiatherosclerotic effects of tumor necrosis factor-α (TNF-α) blockade in patients with systemic inflammatory states are not conclusively demonstrated, which suggests that effects depend on the cause of inflammation. Macrophage LRP1 (low-density lipoprotein receptor–related protein 1) and apoE contribute to inflammation through different pathways. We studied the antiatherosclerosis effects of TNF-α blockade in hyperlipidemic mice lacking either LRP1 (MΦLRP1 −/− ) or apoE from macrophages. Approach and Results—: Lethally irradiated low-density lipoprotein receptor (LDLR) −/− mice were reconstituted with bone marrow from either wild-type, MΦLRP1 −/− , apoE −/− or apoE −/− /MΦLRP1 −/− (DKO) mice, and then treated with the TNF-α inhibitor adalimumab while fed a Western-type diet. Adalimumab reduced plasma TNF-α concentration, suppressed blood ly6C hi monocyte levels and their migration into the lesion, and reduced lesion cellularity and inflammation in both wild-type→LDLR −/− and apoE −/− →LDLR −/− mice. Overall, adalimumab reduced lesion burden by 52% to 57% in these mice. Adalimumab reduced TNF-α and blood ly6C hi monocyte levels in MΦLRP1 −/− →LDLR −/− and DKO→LDLR −/− mice, but it did not suppress ly6C hi monocyte migration into the lesion or atherosclerosis progression. Conclusions—: Our results show that TNF-α blockade exerts antiatherosclerotic effects that are dependent on the presence of macrophage LRP1.

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  • Within the tumor microenvironment, efferocytosis aids in clearing dead cells and modulates immune responses by secreting anti-inflammatory cytokines.

    “Within the TME, efferocytosis aids in clearing dead cells and modulates immune responses by secreting anti-inflammatory cytokines.21”

    From Macrophage efferocytosis mediated by the TP63-RAC2 pathway promotes immunosuppressive remodeling in esophageal cancer (2026) · cites this paper as [21]

    The Introduction describes efferocytosis as the clearance of apoptotic cells, and the Results state that efficient efferocytosis promotes anti-inflammatory cytokine production. These passages concern atherosclerotic lesions, not the tumor microenvironment; our copy does not establish the claim in that setting. (LLM, conf=0.88)

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Authors
Zhu, L., Giunzioni, I., Tavori, H., Covarrubias, R., Ding, L., Zhang, Y., Ormseth, M., Major, A. S., Stafford, J. M., Linton, M. F., & Fazio, S.
Affiliations
Oregon Health & Science University (US)
ORCID
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2016-08
Volume
36
Issue
8
Pages
1483-1495
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
DOI
10.1161/atvbaha.116.307736
PMC
PMC5346022
OpenAlex
W2462046607
Cited by
46
References
50
Citations by year
2026: 2 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 8 · 2021: 4 · 2020: 3 · 2019: 5 · 2018: 9 · 2017: 5 · 2016: 1
FWCI
4.04
Type
journal article
Language
en
Open access
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX002223)
  • National Heart, Lung, and Blood Institute (R01HL057986, R01HL132985, T32HL007411)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23AR068443)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
LRP1, macrophages, TNF-α, TNF-alpha blockade, adalimumab, atherosclerosis, atherosclerotic plaque inflammation, Ly6Chi monocytes, apolipoprotein E, LDL receptor, hyperlipidemia, anti-inflammatory therapy
MeSH terms
Adalimumab, Animals, Anti-Inflammatory Agents, Antigens, Ly, Aorta, Aortic Diseases, Apolipoproteins E, Cell Movement, Disease Models, Animal, Drug Resistance, Female, Macrophages, Monocytes, Necrosis, Phenotype, Receptors, LDL, Tumor Necrosis Factor-alpha, Whole-Body Irradiation, Signal Transduction, Bone Marrow Transplantation, Apoptosis, Mice, Knockout, Genetic Predisposition to Disease, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Atherosclerosis, Plaque, Atherosclerotic, Diet, High-Fat

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