Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2017
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| Online Access: | http://hdl.handle.net/1721.1/109352 https://orcid.org/0000-0003-4255-0492 https://orcid.org/0000-0001-5629-4798 |
| _version_ | 1826207371263737856 |
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| author | Yun, Sanguk Budatha, Madhusudhan Coon, Brian G. Cameron, Ryan T. Baillie, George Schwartz, Martin A. Langer, Robert S Anderson, Daniel Griffith Dahlman, James E. |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Yun, Sanguk Budatha, Madhusudhan Coon, Brian G. Cameron, Ryan T. Baillie, George Schwartz, Martin A. Langer, Robert S Anderson, Daniel Griffith Dahlman, James E. |
| author_sort | Yun, Sanguk |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:48:17Z |
| format | Article |
| id | mit-1721.1/109352 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:48:17Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1093522022-09-28T16:20:45Z Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling Yun, Sanguk Budatha, Madhusudhan Coon, Brian G. Cameron, Ryan T. Baillie, George Schwartz, Martin A. Langer, Robert S Anderson, Daniel Griffith Dahlman, James E. Massachusetts Institute of Technology. Institute for Medical Engineering & Science Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Dahlman, James Langer, Robert S Anderson, Daniel Griffith 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. United States. National Institutes of Health (5R01HL75092) National Science Foundation (U.S.). Materials Research Science and Engineering Centers (Program) (MR/J007412/1) 2017-05-25T19:29:11Z 2017-05-25T19:29:11Z 2016-09 2016-08 Article http://purl.org/eprint/type/JournalArticle 1465-7392 1476-4679 http://hdl.handle.net/1721.1/109352 Yun, Sanguk; Budatha, Madhusudhan; Dahlman, James E.; Coon, Brian G.; Cameron, Ryan T.; Langer, Robert; Anderson, Daniel G.; Baillie, George and Schwartz, Martin A. “Interaction Between Integrin Α5 and PDE4D Regulates Endothelial Inflammatory Signalling.” Nature Cell Biology 18, no. 10 (September 2016): 1043–1053 © 2016 Macmillan Publishers Limited, part of Springer Nature https://orcid.org/0000-0003-4255-0492 https://orcid.org/0000-0001-5629-4798 en_US http://dx.doi.org/10.1038/ncb3405 Nature Cell Biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Yun, Sanguk Budatha, Madhusudhan Coon, Brian G. Cameron, Ryan T. Baillie, George Schwartz, Martin A. Langer, Robert S Anderson, Daniel Griffith Dahlman, James E. Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling |
| title | Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling |
| title_full | Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling |
| title_fullStr | Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling |
| title_full_unstemmed | Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling |
| title_short | Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling |
| title_sort | interaction between integrin α5 and pde4d regulates endothelial inflammatory signalling |
| url | http://hdl.handle.net/1721.1/109352 https://orcid.org/0000-0003-4255-0492 https://orcid.org/0000-0001-5629-4798 |
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