Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling

Nat Cell Biol. 2016 Oct;18(10):1043-53. doi: 10.1038/ncb3405. Epub 2016 Sep 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use
  • Atherosclerosis / metabolism
  • Basement Membrane / metabolism
  • Cells, Cultured
  • Collagen / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Endothelial Cells / metabolism*
  • Extracellular Matrix / metabolism
  • Fibronectins / metabolism*
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism*
  • Integrin alpha5 / metabolism*
  • Mice
  • Signal Transduction*

Substances

  • Anti-Inflammatory Agents
  • Fibronectins
  • Integrin alpha5
  • Collagen
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4D protein, human