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The interaction of ceramide 1-phosphate with group IVA cytosolic phospholipase A2 coordinates acute wound healing and repair.
Science Signaling ( IF 7.3 ) Pub Date : 2019-12-03 , DOI: 10.1126/scisignal.aav5918
H Patrick MacKnight 1, 2 , Daniel J Stephenson 1, 2 , L Alexis Hoeferlin 2 , Savannah D Benusa 3 , James T DeLigio 1, 2 , Kenneth D Maus 1 , Anika N Ali 1 , Jennifer S Wayne 4 , Margaret A Park 1, 2, 5 , Edward H Hinchcliffe 6 , Rhoderick E Brown 6 , John J Ryan 7 , Robert F Diegelmann 2 , Charles E Chalfant 1, 2, 5, 8
Affiliation  

The sphingolipid ceramide 1-phosphate (C1P) directly binds to and activates group IVA cytosolic phospholipase A2 (cPLA2α) to stimulate the production of eicosanoids. Because eicosanoids are important in wound healing, we examined the repair of skin wounds in knockout (KO) mice lacking cPLA2α and in knock-in (KI) mice in which endogenous cPLA2α was replaced with a mutant form having an ablated C1P interaction site. Wound closure rate was not affected in the KO or KI mice, but wound maturation was enhanced in the KI mice compared to that in wild-type controls. Wounds in KI mice displayed increased infiltration of dermal fibroblasts into the wound environment, increased wound tensile strength, and a higher ratio of type I:type III collagen. In vitro, primary dermal fibroblasts (pDFs) from KI mice showed substantially increased collagen deposition and migration velocity compared to pDFs from wild-type and KO mice. KI mice also showed an altered eicosanoid profile of reduced proinflammatory prostaglandins (PGE2 and TXB2) and an increased abundance of certain hydroxyeicosatetraenoic acid (HETE) species. Specifically, an increase in 5-HETE enhanced dermal fibroblast migration and collagen deposition. This gain-of-function role for the mutant cPLA2α was also linked to the relocalization of cPLA2α and 5-HETE biosynthetic enzymes to the cytoplasm and cytoplasmic vesicles. These findings demonstrate the regulation of key wound-healing mechanisms in vivo by a defined protein-lipid interaction and provide insights into the roles that cPLA2α and eicosanoids play in orchestrating wound repair.



中文翻译:

神经酰胺1-磷酸与IVA组胞质磷脂酶A2的相互作用可协调急性伤口的愈合和修复。

的鞘脂神经酰胺-1-磷酸(C1P)直接结合并激活组IVA胞浆型磷脂酶甲2(与cPLA 2 α)生产花生酸类的刺激。由于花生酸类在伤口愈合重要的是,我们研究皮肤创伤修复基因敲除缺乏与cPLA(KO)小鼠2 α和敲入(KI)小鼠中的内源性与cPLA 2用具有消融的C1P相互作用位点的突变形式代替α。伤口闭合率在KO或KI小鼠中不受影响,但与野生型对照组相比,KI小鼠的伤口成熟度提高。KI小鼠的伤口表现出真皮成纤维细胞向伤口环境的浸润增加,伤口抗张强度增加以及I型:III型胶原的比例更高。在体外,与野生型和KO小鼠的pDFs相比,KI小鼠的初级皮肤成纤维细胞(pDFs)胶原蛋白的沉积和迁移速度显着提高。KI小鼠还显示减少的促炎性前列腺素(PGE 2和TXB 2)和某些羟基二十碳四烯酸(HETE)种类的丰度增加。具体而言,5-HETE的增加增强了皮肤成纤维细胞的迁移和胶原蛋白的沉积。这个增益的功能作用,为突变体与cPLA 2 α也被链接到与cPLA的重定位2 α和5-HETE生物合成酶的细胞质和细胞质囊泡。这些发现由定义的蛋白-脂质相互作用表明在体内键伤口愈合机制的调节和提供深入了解其CPLa中的角色2 α和类二十烷酸在编排伤口修复播放。

更新日期:2019-12-04
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