Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling

Yun, S., Budatha, M., Dahlman, J. E., Coon, B. G., Cameron, R. T., Langer, R., Anderson, D. G., Baillie, G. and Schwartz, M. A. (2016) Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling. Nature Cell Biology, 18(10), pp. 1043-1053. (doi:10.1038/ncb3405) (PMID:27595237) (PMCID:PMC5301150)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baillie, Professor George and Cameron, Mr Ryan
Authors: Yun, S., Budatha, M., Dahlman, J. E., Coon, B. G., Cameron, R. T., Langer, R., Anderson, D. G., Baillie, G., and Schwartz, M. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Nature Cell Biology
Publisher:Nature Publishing Group
ISSN:1465-7392
ISSN (Online):1476-4679
Published Online:05 September 2016
Copyright Holders:Copyright © 2016 Macmillan Publishers Limited
First Published:First published in Nature Cell Biology 18(10): 1043-1053
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
588611cAMP phosphodiesterase-4: signalling complexes, regulation and potential therapeutic targets.George BaillieMedical Research Council (MRC)MR/J007412/1RI CARDIOVASCULAR & MEDICAL SCIENCES