Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling
Open accessAbstract
Atherosclerosis is primarily a disease of lipid metabolism and inflammation; however, it is also closely associated with endothelial extracellular matrix (ECM) remodelling, with fibronectin accumulating in the laminin-collagen basement membrane. To investigate how fibronectin modulates inflammation in arteries, we replaced the cytoplasmic tail of the fibronectin receptor integrin α5 with that of the collagen/laminin receptor integrin α2. This chimaera suppressed inflammatory signalling in endothelial cells on fibronectin and in knock-in mice. Fibronectin promoted inflammation by suppressing anti-inflammatory cAMP. cAMP was activated through endothelial prostacyclin secretion; however, this was ECM-independent. Instead, cells on fibronectin suppressed cAMP via enhanced phosphodiesterase (PDE) activity, through direct binding of integrin α5 to phosphodiesterase-4D5 (PDE4D5), which induced PP2A-dependent dephosphorylation of PDE4D5 on the inhibitory site Ser651. In vivo knockdown of PDE4D5 inhibited inflammation at athero-prone sites. These data elucidate a molecular mechanism linking ECM remodelling and inflammation, thereby identifying a new class of therapeutic targets.
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α5β1-integrin signaling mediates harmful endothelial remodeling in a mouse atherosclerosis model.
“Interestingly, α5β1-integrin signaling has been recently linked to chronic inflammation as it was shown to mediate harmful endothelial remodeling in a mouse atherosclerosis model (14).”
From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [14]
Switching from α5β1 signaling to α2β1 signaling inhibited the formation of atheromas in hypercholesterolemic Apoe-deficient mice.
“switching from α5β1 signaling to α2β1 signaling inhibited the formation of atheromas in hypercholesterolemic apolipoprotein E (Apoe)-deficient mice (14).”
From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [14]
α5β1-integrin regulates endothelial activation in chronic inflammation.
“others have shown that α5β1-integrin regulates endothelial activation in chronic inflammation (14).”
From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [14]
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References 71 · Cited by 96
- Authors
- Yun, S., Budatha, M., Dahlman, J. E., Coon, B. G., Cameron, R. T., Langer, R., Anderson, D. G., Baillie, G., & Schwartz, M. A.
- Affiliations
- Yale University (US)
- Harvard–MIT Division of Health Sciences and Technology (US)
- University of Glasgow (GB)
- Corresponding author
- Schwartz, Martin A.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2016-09-05
- Volume
- 18
- Issue
- 10
- Pages
- 1043-1053
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC5301150
- OpenAlex
- W2516557409
- Cited by
- 96
- References
- 71
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 6 · 2023: 10 · 2022: 7 · 2021: 14 · 2020: 11 · 2019: 14 · 2018: 15 · 2017: 7
- FWCI
- 6.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- PMC
- Funders
- Yale University
- Pohang University of Science and Technology
- National Institutes of Health (UL1TR001863)
- Medical Research Council (MR/J007412/1)
- National Heart, Lung, and Blood Institute (R01HL075092)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK059635)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- integrin alpha5, endothelial inflammation, fibronectin, extracellular matrix remodeling, cAMP signaling, prostacyclin, PP2A dephosphorylation, atherosclerosis, endothelial cells
- MeSH terms
- Animals, Anti-Inflammatory Agents, Basement Membrane, Cells, Cultured, Collagen, Extracellular Matrix, Fibronectins, Humans, Inflammation, Signal Transduction, Integrin alpha5, Endothelial Cells, Atherosclerosis, Mice, Cyclic Nucleotide Phosphodiesterases, Type 4
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