Autophagy protein LC3 regulates the fibrosis of hypertrophic scar by controlling Bcl-xL in dermal fibroblasts.
Autophagy protein LC3 regulates the fibrosis of hypertrophic scar by controlling Bcl-xL in dermal fibroblasts.
复制标题
自噬蛋白LC3通过控制真皮成纤维细胞中的Bcl-xL调节增生性疤痕纤维化
DOI：
10.18632/oncotarget.20771
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发表时间：
2017-11-07
期刊：
影响因子：
--
通讯作者：
Guan H
中科院分区：
文献类型：
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作者：
Shi J;Shi S;Wu B;Zhang J;Li Y;Wu X;Zhang J;Wang K;Zhao B;Cai W;Bai X;Hu D;Guan H
增生性瘢痕（HS）是一种严重的皮肤纤维化疾病，其特征是细胞过度增生和细胞外基质（ECM）成分沉积。自噬是细胞维持、分化、发育和内环境稳定所必需的一个严格调控的生理过程。然而，在HS的形成过程中，自噬是否以及如何在真皮成纤维细胞中受到调节仍远未阐明。本研究检测了HS和正常皮肤（NS）的自噬能力，探索并验证了HS来源的成纤维细胞（HSFs）自噬的关键调控分子，并利用兔耳瘢痕模型进行了验证。透射电子显微镜（TEM）和免疫染色数据显示，LC 3阳性细胞和自噬体在HS/HSFs组更密集相对于NS/NSFs组。敲低LC 3（shLC 3）可显著抑制HSF中I型胶原（Col 1，p <0.0 1）和III型胶原（Col 3，p <0.0 1）的表达，从而抑制HSF纤维化。抗自噬的shLC 3显示是Bcl-xL依赖性的，而不是Bcl-2依赖性的，并且Bcl-xL（sibcl-xL）的沉默显著增加了HSF的凋亡（p <0.01）。免疫荧光结果显示，shLC3并不抑制α-SMA蛋白的表达，而是改变了α-SMA在HSF中的结构排列。sibcl-xL表明Bcl-xL是参与HSFs自噬的关键信号分子。更重要的是，shLC3和sibcl-xL都明显改善了兔耳瘢痕的外观和结构，并减少了兔耳上的瘢痕形成。因此，LC 3蛋白加工的异常影响了HS中的自噬，可能与其在创伤修复中的发病机制有关。LC3通过调控Bcl-xL在HSFs中的表达来调节HS纤维化。因此，Bcl-xL可能作为一个潜在的分子靶点，为HS的治疗提供了一种新的策略。
Hypertrophic scar (HS) is a serious skin fibrotic disease characterized by excessive hypercellularity and extracellular matrix (ECM) component deposition. Autophagy is a tightly regulated physiological process essential for cellular maintenance, differentiation, development and homeostasis. However, during the formation of HS, whether and how autophagy is regulated in dermal fibroblasts are still far from elucidated. Here we detected the autophagic capacity in HS and normal skin (NS) counterparts, explored and verified the key regulatory molecules of autophagy in HS-derived fibroblasts (HSFs), and validated the data using rabbit ear scar model. Transmission electron microscopy (TEM) and immunostaining data showed that LC3-positive cells and autophagosomes in HS/HSFs were more intensive relative to those in NS/NSFs groups. Knockdown of LC3 (shLC3) could significantly block the expressionof type I collagen (Col 1, p < 0.01) and type III collagen (Col 3, p < 0.01) and thus inhibit the fibrosis of HSFs. shLC3 resistant to autophagy was shown to be Bcl-xL-, not Bcl-2-dependent, and silencing of Bcl-xL (sibcl-xL) significantly increased apoptosis of HSFs (p < 0.01). Immunofluorescence results showed that instead of inhibiting α-SMA protein expression, shLC3 could change its architecture arrangement in HSFs. sibcl-xL showed that Bcl-xL was a key signaling molecule involved in HSFs autophagy. More importantly, both shLC3 and sibcl-xL obviously improved the appearance and architecture of the rabbit ear scar, and reduced scar formation on the rabbit ear. Therefore, the aberration of LC3 protein processing compromised autophagy in HS might associate with its pathogenesis in wound repair. LC3 regulated HS fibrosis by controlling the expression of Bcl-xL in HSFs. Thus, Bcl-xL might serve as a potential molecular target, providing a novel strategy for HS therapy.