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 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.
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, Connecticut 06520, USA.
Sanguk
S
Yun
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, Connecticut 06520, USA.
Madhusudhan
M
Budatha
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
James E
JE
Dahlman
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, Connecticut 06520, USA.
Brian G
0000-0002-4516-0193
BG
Coon
Institute of Cardiovascular and Medical Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
Ryan T
RT
Cameron
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Robert
R
Langer
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Daniel G
DG
Anderson
Institute of Cardiovascular and Medical Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
George
G
Baillie
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, Connecticut 06520, USA.|Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06520, USA.|Department of Cell Biology, Yale University, New Haven, Connecticut 06520, USA.
Martin A
0000-0002-2071-1243
MA
Schwartz
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D050197:Atherosclerosis / Q000378:metabolism; D001485:Basement Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D039482:Integrin alpha5 / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction
D000893:Anti-Inflammatory Agents; D005353:Fibronectins; D039482:Integrin alpha5; D003094:Collagen; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human