Interaction between integrin α 5 and PDE4D regulates endothelial inflammatory signalling

Sanguk Yun, Madhusudhan Budatha, James E. Dahlman, Brian G. Coon, Ryan T. Cameron, Robert Langer, Daniel G. Anderson, George Baillie, Martin A. Schwartz

Research output: Contribution to journalArticle

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1043-1053
Number of pages11
JournalNature Cell Biology
Volume18
Issue number10
DOIs
StatePublished - Sep 28 2016
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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    Yun, S., Budatha, M., Dahlman, J. E., Coon, B. G., Cameron, R. T., Langer, R., Anderson, D. G., Baillie, G., & Schwartz, M. A. (2016). Interaction between integrin α 5 and PDE4D regulates endothelial inflammatory signalling. Nature Cell Biology, 18(10), 1043-1053. https://doi.org/10.1038/ncb3405