Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling
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Author(s)
Yun, Sanguk
Budatha, Madhusudhan
Coon, Brian G.
Cameron, Ryan T.
Baillie, George
Schwartz, Martin A.
Langer, Robert S
Anderson, Daniel Griffith
Dahlman, James E.
Date Issued
September 2016
Journal
Nature Cell Biology
Publisher
Nature Publishing Group
Citation
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
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Author's final manuscript
Abstract
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.
MIT Department
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
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DOI of Published Version
https://doi.org/10.1038/ncb3405
