The role of the FPR2/ALX receptor in atherosclerosis development and plaque stability
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AIMS: The formyl peptide receptor (FPR) subtype FPR2/ALX transduces pro-inflammatory responses and participates in the resolution of inflammation depending on activation. The aim of the present study was to unravel the role of FPR2/ALX signalling in atherosclerosis. METHODS AND RESULTS: Expression of FPR2/ALX was analysed in 127 human carotid atherosclerotic lesions and revealed that this receptor was expressed on macrophages, smooth muscle cells (SMCs), and endothelial cells. Furthermore, FPR2/ALX mRNA levels were significantly up-regulated in atherosclerotic lesions compared with healthy vessels. In multiple regression, age, creatinine, and clinical signs of increased cerebral ischaemia were independent predictors of FPR2/ALX expression. To provide mechanistic insights into these observations, we generated Ldlr(-/-)xFpr2(-/-) mice, which exhibited delayed atherosclerosis development and less macrophage infiltration compared with Ldlr(-/-)xFpr2(+/+) mice. These findings were reproduced by transplantation of Fpr2(-/-) bone marrow into Ldlr(-/-) mice and further extended by in vitro experiments, demonstrating a lower inflammatory state in Fpr2(-/-) macrophages. FPR2/ALX expression correlated with chemo- and cytokines in human atherosclerotic lesions and leucocytes. Finally, atherosclerotic lesions in Ldlr(-/-)xFpr2(-/-) mice exhibited decreased collagen content, and Fpr2(-/-) SMCs exhibited a profile of increased collagenase and decreased collagen production pathways. CONCLUSION: FPR2/ALX is proatherogenic due to effects on bone marrow-derived cells, but promoted a more stable plaque phenotype through effects on SMCs. Taken together, these results suggest a dual role of FPR2/ALX signalling in atherosclerosis by way of promoting disease progression and but increasing plaque stability.
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ALX/FPR2 and ChemR23 are expressed in human aortic, coronary, and carotid atherosclerotic lesions, indicating that their pro-resolving ligands act locally within the vascular wall.
“These receptors are expressed in human aortic, coronary and carotid atherosclerotic lesions104–106, indicating that their pro-resolving ligands exert local effects within the vascular wall (TABLE 1).”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [104]
Genetic targeting of the murine ALX/FPR2 homologue in hyperlipidaemic mice showed that ALX/FPR2 deficiency reduced atherosclerosis consistently in different mouse models.
“A study on genetic targeting of the murine ALX/FPR2 homologue in hyperlipidaemic mice provided arguments in favour of this hypothesis by showing that ALX/FPR2 deficiency reduced atherosclerosis consistently in different mouse models99,104.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [104]
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- Authors
- Petri, M. H., Laguna-Fernández, A., Gonzalez-Diez, M., Paulsson-Berne, G., Hansson, G. K., & Bäck, M.
- Affiliations
- Karolinska University Hospital (SE)
- Corresponding author
- Bäck, Magnus
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-10-23
- Volume
- 105
- Issue
- 1
- Pages
- 65-74
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- PMC
- PMC4277257
- OpenAlex
- W2000987582
- Cited by
- 125
- References
- 44
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 9 · 2023: 13 · 2022: 20 · 2021: 14 · 2020: 7 · 2019: 10 · 2018: 13 · 2017: 10 · 2016: 7 · 2015: 6 · 2014: 2
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Cardiovascular Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Stockholms Läns Landsting (20120297)
- Vetenskapsrådet (2011-02988, 20120827, 2012-02577, 20120474)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- FPR2/ALX, formyl peptide receptor, atherosclerosis, plaque stability, macrophage infiltration, smooth muscle cells, collagen synthesis, collagenase, inflammation, bone marrow-derived cells, Ldlr knockout mice, cerebral ischemia
- MeSH terms
- Aged, Aged, 80 and over, Animals, Carotid Artery Diseases, Collagen, Female, Humans, Macrophages, Male, Middle Aged, Receptors, LDL, RNA, Messenger, Signal Transduction, Up-Regulation, Bone Marrow Transplantation, Carotid Stenosis, Mice, Knockout, Myocytes, Smooth Muscle, Receptors, Formyl Peptide, Receptors, Lipoxin, Atherosclerosis, Mice, Plaque, Atherosclerotic
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