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Cited by 18Phagocytosis and Immune RegulationAtherosclerosis and Cardiovascular DiseasesCholesterol and Lipid Metabolism

Cyclophilin A Impairs Efferocytosis and Accelerates Atherosclerosis by Overexpressing CD 47 and Down-Regulating Calreticulin

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Anandan, Vinitha, Thulaseedharan, Thushara, Suresh Kumar, Aishwarya, Chandran Latha, Karthika, Revikumar, Amjesh, Mullasari, Ajit, Kartha, Chandrasekharan C., Jaleel, Abdul +1 more·2021·Cells
DOI 10.3390/cells10123598PMC PMC8700718
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Abstract

Impairment of efferocytosis in apoptotic macrophages is a known determinant of the severity of atherosclerosis and the vulnerability of plaques to rupture. The precise mechanisms involved in impaired efferocytosis are unclear. Given the well-recognized role of the inflammatory cytokine cyclophilin A (Cyp A) in modulating several atherogenic mechanisms in high-glucose primed monocytes, we investigated the role of Cyp A in macrophage efferocytosis. The efficiency of efferocytosis in RAW 264.7 macrophages grown in vitro and primed with cyclophilin A was assessed using flow cytometry and confocal assays. Cholesterol content in cells was measured using cell-based cholesterol efflux assay. Proteomic analysis and bioinformatics tools were employed to decipher the link between cyclophilin A and the known ligand receptors involved in efferocytosis. Cyclophilin A was found to impair efferocytosis in apoptotic macrophages by reducing ABCA1-mediated cholesterol efflux in foam cells derived from macrophages. Cyclophilin A-primed macrophages showed an increase in expression of the don’t-eat-me signal CD 47 and a decrease in the expression of the eat-me signal, calreticulin. Phagocytosis was restored upon silencing of cyclophilin A. New Zealand white rabbits were fed a high-fat diet, and lesions in their aortae were analyzed histologically for evidence of atherosclerosis and the expression of Cyp A, CD 47 and calreticulin, the ligand receptor involved in efferocytosis. Gene and protein expressions in aortae and macrophages were analyzed by real-time PCR and Western blotting. Cyclophilin A, via its effects on the expression of CD 47 and calreticulin, impairs efferocytosis in apoptotic macrophages. Together with its impact on cholesterol efflux from macrophages, these effects can amplify other mechanisms of Cyp A in accelerating the progression of atherosclerosis.

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Authors
Anandan, V., Thulaseedharan, T., Suresh Kumar, A., Chandran Latha, K., Revikumar, A., Mullasari, A., Kartha, C. C., Jaleel, A., & Ramachandran, S.
Affiliations
  • Manipal Academy of Higher Education (IN)
  • Rajiv Gandhi Centre for Biotechnology (IN)
  • Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
  • Madras Medical Mission (IN)
  • Department of Neurology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi 682041, Kerala, India
Corresponding author
Ramachandran, Surya
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2021-12-20
Volume
10
Issue
12
Pages
3598
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells10123598
PMC
PMC8700718
OpenAlex
W4200520442
Cited by
18
References
1
Citations by year
2026: 3 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 5
FWCI
1.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Kerala State Council for Science, Technology and Environment (034/YIPB/KBC/2016/KSCSTE)
  • Madras Medical Mission (MMM/001/2017)
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
cyclophilin A, efferocytosis, atherosclerosis, CD47, calreticulin, ABCA1, cholesterol efflux, foam cells, phagocytosis, high-fat diet, plaque vulnerability
MeSH terms
RAW 264.7 Cells, Animals, Foam Cells, Models, Biological, Phagocytosis, Rabbits, Down-Regulation, Apoptosis, Cyclophilin A, Calreticulin, Atherosclerosis, Mice, CD47 Antigen, Diet, High-Fat, ATP Binding Cassette Transporter 1

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