Yun Sanguk, Budatha Madhusudhan, Dahlman James E, Coon Brian G, Cameron Ryan T, Langer Robert, Anderson Daniel G, Baillie George, Schwartz Martin A
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, Connecticut 06520, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Nat Cell Biol. 2016 Oct;18(10):1043-53. doi: 10.1038/ncb3405. Epub 2016 Sep 5.
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.
动脉粥样硬化主要是一种脂质代谢和炎症性疾病；然而，它也与内皮细胞外基质（ECM）重塑密切相关，纤连蛋白在层粘连蛋白 - 胶原蛋白基底膜中积累。为了研究纤连蛋白如何调节动脉炎症，我们将纤连蛋白受体整合素α5的细胞质尾巴替换为胶原蛋白/层粘连蛋白受体整合素α2的细胞质尾巴。这种嵌合体抑制了纤连蛋白上内皮细胞以及基因敲入小鼠中的炎症信号传导。纤连蛋白通过抑制抗炎性环磷酸腺苷（cAMP）来促进炎症。cAMP通过内皮前列环素分泌而被激活；然而，这与ECM无关。相反，纤连蛋白上的细胞通过增强磷酸二酯酶（PDE）活性来抑制cAMP，这是通过整合素α5与磷酸二酯酶 - 4D5（PDE4D5）直接结合实现的，后者诱导PP2A依赖的PDE4D5在抑制位点Ser651处的去磷酸化。体内敲低PDE4D5可抑制动脉粥样硬化易患部位的炎症。这些数据阐明了一种将ECM重塑与炎症联系起来的分子机制，从而确定了一类新的治疗靶点。
