MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis
Open accessAbstract
Atherothrombotic vascular disease is often triggered by a distinct type of atherosclerotic lesion that displays features of impaired inflammation resolution, notably a necrotic core and thinning of a protective fibrous cap that overlies the core. A key cause of plaque necrosis is defective clearance of apoptotic cells, or efferocytosis, by lesional macrophages, but the mechanisms underlying defective efferocytosis and its possible links to impaired resolution in atherosclerosis are incompletely understood. Here, we provide evidence that proteolytic cleavage of the macrophage efferocytosis receptor c-Mer tyrosine kinase (MerTK) reduces efferocytosis and promotes plaque necrosis and defective resolution. In human carotid plaques, MerTK cleavage correlated with plaque necrosis and the presence of ischemic symptoms. Moreover, in fat-fed LDL receptor-deficient (Ldlr-/-) mice whose myeloid cells expressed a cleavage-resistant variant of MerTK, atherosclerotic lesions exhibited higher macrophage MerTK, lower levels of the cleavage product soluble Mer, improved efferocytosis, smaller necrotic cores, thicker fibrous caps, and increased ratio of proresolving versus proinflammatory lipid mediators. These findings provide a plausible molecular-cellular mechanism that contributes to defective efferocytosis, plaque necrosis, and impaired resolution during the progression of atherosclerosis.
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Soluble MER rises in advancing atherosclerosis in mice and humans and can compete with MERTK for GAS6 and protein S binding, thereby compromising lesional efferocytosis.
“Levels of the cleaved product, soluble MER, increase in advancing atherosclerosis in both mice and humans and can compete with MERTK for binding of GAS6 and protein S and thereby compromise efferocytosis in the lesion162.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [162]
Athero-prone mice engineered to express cleavage-resistant MERTK are less prone to develop necrotic cores than control mice.
“Athero-prone mice genetically engineered to express cleavage-resistant MERTK show a decreased propensity to develop necrotic cores compared with control mice162.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [162]
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Self-citation
- Authors
- Cai, B., Thorp, E. B., Doran, A. C., Sansbury, B. E., Daemen, M. J. A. P., Dorweiler, B., Spite, M., Fredman, G., & Tabas, I.
- Affiliations
- Columbia University (US)
- Northwestern University (US)
- Brigham and Women's Hospital (US)
- Amsterdam UMC Location University of Amsterdam (NL)
- Johannes Gutenberg University Mainz (DE)
- Albany Medical College (US)
- Corresponding author
- Tabas, Ira
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2017-01-09
- Volume
- 127
- Issue
- 2
- Pages
- 564-568
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5272169
- OpenAlex
- W2569227792
- Cited by
- 262
- References
- 39
- Citations by year
- 2026: 37 · 2025: 34 · 2024: 38 · 2023: 27 · 2022: 23 · 2021: 28 · 2020: 18 · 2019: 21 · 2018: 19 · 2017: 16 · 2016: 1
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Health Research Alliance (cc-by)
- Funders
- American Heart Association (T32 HL007854)
- National Institutes of Health (UL1TR001422, HL119587, HL007854)
- National Heart, Lung, and Blood Institute (R01HL122309, R01HL132412, R01HL140554, R01HL127464, R00HL119587, K99HL119587, P01HL087123, R01HL075662, R01HL106173, T32HL007854)
- National Institute of General Medical Sciences (P01GM095467)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- MERTK, efferocytosis, plaque necrosis, atherosclerosis, inflammation resolution, macrophages, necrotic core, fibrous cap, carotid plaque, specialized pro-resolving mediators, Ldlr-deficient mice, atherothrombosis
- MeSH terms
- c-Mer Tyrosine Kinase, Animals, Carotid Artery Diseases, Female, Humans, Male, Necrosis, Proto-Oncogene Proteins, Receptors, LDL, Mice, Knockout, Receptor Protein-Tyrosine Kinases, Mice, Plaque, Atherosclerotic, Proteolysis
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