Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice
Open accessAbstract
Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes 1 . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL 2-4. Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr-/- background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr-/- mice, Ldlr -/- E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis.
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In transgenic mice expressing a single-chain variable fragment of an oxPL-recognizing natural antibody, macrophages showed decreased oxLDL uptake, decreased oxPL-induced inflammation, and reduced atherosclerosis compared with controls.
“macrophages of transgenic mice expressing a single-chain variable fragment of an oxPL-recognizing natural antibody showed decreased uptake of oxLDL compared with macrophages from control mice51. Moreover, these mice had decreased oxPL-induced inflammation and reduced atherosclerosis compared with the control mice.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [51]
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- Authors
- Que, X., Hung, M.-Y., Yeang, C., Gonen, A., Prohaska, T. A., Sun, X., Diehl, C., Määttä, A., Gaddis, D. E., Bowden, K., Pattison, J., MacDonald, J. G., Ylä-Herttuala, S., Mellon, P. L., Hedrick, C. C., Ley, K., Miller, Y. I., Glass, C. K., Peterson, K. L., Binder, C. J., Tsimikas, S., & Witztum, J. L.
- Affiliations
- University of California San Diego (US)
- University of Eastern Finland (FI)
- La Jolla Institute for Immunology (US)
- The University of Texas Southwestern Medical Center (US)
- Austrian Academy of Sciences (AT)
- Corresponding author
- Witztum, Joseph L.
- ORCID
- Venue
- Nature
- Published
- 2018-06
- Volume
- 558
- Issue
- 7709
- Pages
- 301-306
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6033669
- OpenAlex
- W2806741586
- Cited by
- 529
- References
- 40
- Citations by year
- 2026: 45 · 2025: 63 · 2024: 60 · 2023: 65 · 2022: 72 · 2021: 74 · 2020: 71 · 2019: 61 · 2018: 16 · 2015: 1 · 2012: 1
- FWCI
- 23.85
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-07-16)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL055798, R01HL119828, R01HL112276, R35HL135737, P01HL020948, P01HL088093, R01HL086559, P01HL136275)
- National Cancer Institute (P30CA023100)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK044838, P30DK063491, T32DK007044)
- National Institute of Environmental Health Sciences (P42ES010337)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD012303, R01HD082567)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- oxidized phospholipids, oxidized LDL, atherosclerosis, hypercholesterolemia, scFv, macrophage uptake, lipid peroxidation, aortic valve calcification, aortic stenosis, hepatic steatosis, serum amyloid A, systemic inflammation, transgenic mice, apolipoprotein E
- MeSH terms
- Animals, Aortic Valve Stenosis, Cholesterol, Fatty Liver, Female, Hypercholesterolemia, Immunoglobulin M, Inflammation, Lipoproteins, LDL, Mice, Inbred C57BL, Mice, Transgenic, Oxidation-Reduction, Phospholipids, Phosphorylcholine, Receptors, LDL, Apoptosis, Macrophages, Peritoneal, Disease Progression, Atherosclerosis, Mice, Single-Chain Antibodies
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