| First Author | Yun S | Year | 2016 |
| Journal | Nat Cell Biol | Volume | 18 |
| Issue | 10 | Pages | 1043-53 |
| PubMed ID | 27595237 | Mgi Jnum | J:266785 |
| Mgi Id | MGI:6256880 | Doi | 10.1038/ncb3405 |
| Citation | Yun S, et al. (2016) Interaction between integrin alpha5 and PDE4D regulates endothelial inflammatory signalling. Nat Cell Biol 18(10):1043-53 |
| abstractText | 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 alpha5 with that of the collagen/laminin receptor integrin alpha2. 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 alpha5 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. |
