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Cited by 127Atherosclerosis and Cardiovascular DiseasesCerebrovascular and Carotid Artery DiseasesCholesterol and Lipid Metabolism

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The role of the FPR2/ALX receptor in atherosclerosis development and plaque stability

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Petri, Marcelo H., Laguna-Fernández, Andrés, Gonzalez-Diez, Maria, Paulsson-Berne, Gabrielle, Hansson, Göran K., Bäck, Magnus·2015·Cardiovascular Research
DOI 10.1093/cvr/cvu224PMC PMC4277257
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Abstract

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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Crossref · 10.1093/cvr/cvu224

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Figure 1 (A) FPR2/ALX mRNA expression in healthy arteries (N = 10) and atherosclerotic plaques (N = 127). Results are expressed in arbitrary units and the horizontal line represents the mean. *P < 0.05 compared with healthy samples. (B) The associations between mRNA levels of FPR2/ALX and different leucocyte markers. (C) Representative IF staining of human atherosclerotic plaques from the carotid artery. The FPR2/ALX protein (red) co-localized with the following markers (green) in atherosclerotic plaques: CD163, α-smooth muscle actin, vWF, and CD31.
Figure 1 (A) FPR2/ALX mRNA expression in healthy arteries (N = 10) and atherosclerotic plaques (N = 127). Results are expressed in arbitrary units and the horizontal line represents the mean. *P < 0.05 compared with healthy samples. (B) The associations between mRNA levels of FPR2/ALX and different leucocyte markers. (C) Representative IF staining of human atherosclerotic plaques from the carotid artery. The FPR2/ALX protein (red) co-localized with the following markers (green) in atherosclerotic plaques: CD163, α-smooth muscle actin, vWF, and CD31.CC BY-NC · PubMed Central
Figure 2 Atherosclerotic lesion size in aortic roots (A) and aortic arch (B) derived from either Ldlr−/−xFpr2+/+ (closed circles) or Ldlr−/−xFpr2−/− (open circles) after different times on HFD. Results are expressed as per cent positive staining, and lines represent mean ± SEM. *P < 0.05 compared with Ldlr−/−xFpr2+/+ at the same time point. Aortic roots: N = 5, 12, 7, and 4 for Ldlr−/−xFpr2+/+ and N = 8, 17, 8, and 5 for Ldlr−/−xFpr2−/− at 8, 12 16, and 20 weeks on HFD, respectively. Aortic arch: N = 7, 15, 10, and 5 for Ldlr−/−xFpr2+/+ and N = 11, 21, 9, and 5 for Ldlr−/−xFpr2−/− at 8, 12, 16, and 20 weeks on HFD, respectively.
Figure 2 Atherosclerotic lesion size in aortic roots (A) and aortic arch (B) derived from either Ldlr−/−xFpr2+/+ (closed circles) or Ldlr−/−xFpr2−/− (open circles) after different times on HFD. Results are expressed as per cent positive staining, and lines represent mean ± SEM. *P < 0.05 compared with Ldlr−/−xFpr2+/+ at the same time point. Aortic roots: N = 5, 12, 7, and 4 for Ldlr−/−xFpr2+/+ and N = 8, 17, 8, and 5 for Ldlr−/−xFpr2−/− at 8, 12 16, and 20 weeks on HFD, respectively. Aortic arch: N = 7, 15, 10, and 5 for Ldlr−/−xFpr2+/+ and N = 11, 21, 9, and 5 for Ldlr−/−xFpr2−/− at 8, 12, 16, and 20 weeks on HFD, respectively.CC BY-NC · PubMed Central
Figure 3 Atherosclerotic lesion size in aortic roots (A) and aortic arch (B) derived from either Ldlr−/−xFpr2+/+ (closed circles, N = 8) or Ldlr−/−xFpr2−/− (open circles, N = 13) after 12 weeks on HFD. Representative micrographs are shown on top. The plaque composition of the aortic roots in terms of CD68 and CD3 is shown in (C). For Picrosirius red collagen staining (D), each symbol represents the average of at least four sections derived from each mouse expressed as fold change relative Ldlr−/−xFpr2+/+. Representative micrographs of each staining are shown in the right side. Results are expressed as mean ± SEM for the indicated units. *P < 0.05.
Figure 3 Atherosclerotic lesion size in aortic roots (A) and aortic arch (B) derived from either Ldlr−/−xFpr2+/+ (closed circles, N = 8) or Ldlr−/−xFpr2−/− (open circles, N = 13) after 12 weeks on HFD. Representative micrographs are shown on top. The plaque composition of the aortic roots in terms of CD68 and CD3 is shown in (C). For Picrosirius red collagen staining (D), each symbol represents the average of at least four sections derived from each mouse expressed as fold change relative Ldlr−/−xFpr2+/+. Representative micrographs of each staining are shown in the right side. Results are expressed as mean ± SEM for the indicated units. *P < 0.05.CC BY-NC · PubMed Central
Figure 4 Atherosclerotic lesion size in aortic roots (A) and aortic arch (B) derived from Ldlr−/− mice receiving BM from either Fpr2+/+ (Ldlr−/−BM Fpr2+/+, closed circles, N = 8) or Fpr2−/− (Ldlr−/−BM Fpr2−/−, open circles, N = 8) donors. Tissue was collected after 20 weeks of HFD. Representative micrographs are also shown on top. The plaque composition of the aortic roots in terms of CD68 and CD3 is shown in (C and D). For Picrosirius red collagen staining, each symbol represents the average of at least four sections derived from each mouse expressed as fold change relative Ldlr−/−BM Fpr2+/+. Representative micrographs of each staining are also shown. Results are expressed as mean ± SEM for the indicated units. *P < 0.05.
Figure 4 Atherosclerotic lesion size in aortic roots (A) and aortic arch (B) derived from Ldlr−/− mice receiving BM from either Fpr2+/+ (Ldlr−/−BM Fpr2+/+, closed circles, N = 8) or Fpr2−/− (Ldlr−/−BM Fpr2−/−, open circles, N = 8) donors. Tissue was collected after 20 weeks of HFD. Representative micrographs are also shown on top. The plaque composition of the aortic roots in terms of CD68 and CD3 is shown in (C and D). For Picrosirius red collagen staining, each symbol represents the average of at least four sections derived from each mouse expressed as fold change relative Ldlr−/−BM Fpr2+/+. Representative micrographs of each staining are also shown. Results are expressed as mean ± SEM for the indicated units. *P < 0.05.CC BY-NC · PubMed Central
Figure 5 (A) The results of real-time PCR for IL-1β, CXCL1, and IL-6 expression in peritoneal macrophages derived from either Fpr2+/+ (close circles) or Fpr2−/− (open circles). Each symbol represents three different experiments using pooled samples from three mice. (B) The correlations of FPR2/ALX mRNA levels with the respective cyto/chemokine mRNA in peripheral blood monocytic cells (PMBC, n = 98) and atherosclerotic lesions (n = 127) derived from patients undergoing carotid endarterectomy. In (C), representative tracings of calcium oscillations in peritoneal macrophages from Fpr2+/+ (dotted line) and Fpr2−/− (continuous line) are shown. These tracings represent the oscillations in the respective cells marked with a white arrow in the right panels, and can be visualized in Supplementary material online, Videos S1 and S2, respectively. (C) The uptake of apoptotic splenocytes by peritoneal macrophages (1 : 2 ratio efferocyte : apoptotic cell), derived from either Fpr2+/+ (black bars) or Fpr2−/− (white bars) mice. Results (mean ± SEM) are expressed as fold change compared with Fpr2+/+ macrophages; n = 5. *P < 0.05.
Figure 5 (A) The results of real-time PCR for IL-1β, CXCL1, and IL-6 expression in peritoneal macrophages derived from either Fpr2+/+ (close circles) or Fpr2−/− (open circles). Each symbol represents three different experiments using pooled samples from three mice. (B) The correlations of FPR2/ALX mRNA levels with the respective cyto/chemokine mRNA in peripheral blood monocytic cells (PMBC, n = 98) and atherosclerotic lesions (n = 127) derived from patients undergoing carotid endarterectomy. In (C), representative tracings of calcium oscillations in peritoneal macrophages from Fpr2+/+ (dotted line) and Fpr2−/− (continuous line) are shown. These tracings represent the oscillations in the respective cells marked with a white arrow in the right panels, and can be visualized in Supplementary material online, Videos S1 and S2, respectively. (C) The uptake of apoptotic splenocytes by peritoneal macrophages (1 : 2 ratio efferocyte : apoptotic cell), derived from either Fpr2+/+ (black bars) or Fpr2−/− (white bars) mice. Results (mean ± SEM) are expressed as fold change compared with Fpr2+/+ macrophages; n = 5. *P < 0.05.CC BY-NC · PubMed Central
Figure 6 (A) Representative confocal IF stainings of FPR2 (red) and α-smooth muscle actin (green) in mSMC derived from either Fpr2+/+ (top) or Fpr2−/− mice (bottom). (B) The results of real-time PCR for collagen 1A (Col1A1), lysyl oxidase (LOX), MMP–13, and tissue inhibitor of MMP (TIMP)-1 in mSMC derived from Fpr2+/+ and Fpr2−/− mice (B; N = 3). *P < 0.05 compared with the respective control in each graph.
Figure 6 (A) Representative confocal IF stainings of FPR2 (red) and α-smooth muscle actin (green) in mSMC derived from either Fpr2+/+ (top) or Fpr2−/− mice (bottom). (B) The results of real-time PCR for collagen 1A (Col1A1), lysyl oxidase (LOX), MMP–13, and tissue inhibitor of MMP (TIMP)-1 in mSMC derived from Fpr2+/+ and Fpr2−/− mice (B; N = 3). *P < 0.05 compared with the respective control in each graph.CC BY-NC · PubMed Central

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Metadata

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
ORCID
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
DOI
10.1093/cvr/cvu224
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
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 › Cardiology and Cardiovascular Medicine › Cerebrovascular and Carotid Artery Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › 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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