Wild-type p53-modulated autophagy and autophagic fibroblast apoptosis inhibit hypertrophic scar formation
Wild-type p53-modulated autophagy and autophagic fibroblast apoptosis inhibit hypertrophic scar formation
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野生型 p53 调节的自噬和自噬成纤维细胞凋亡抑制增生性疤痕形成
DOI：
10.1038/s41374-018-0099-3
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发表时间：
2018-11-01
影响因子：
5
通讯作者：
Guan, Hao
中科院分区：
文献类型：
--
作者：
Shi, Jihong;Xiao, Houan;Guan, Hao
增生性瘢痕是一种严重的皮肤纤维化疾病，增生性瘢痕成纤维细胞（HSFs）的异常活化加剧了其发病机制。我们以前的研究已经证明，HSF中自噬的失调与纤维化有关。然而，关于通过p53调节的自噬调节HS纤维化的知识是有限的。在这里，我们研究了p53调节的自噬对HS纤维化的影响。过表达wtp 53（Adp 53）可促进HSFs的自噬能力，抑制胶原和α-SMA的表达。相反，LC 3（AdLC 3）过表达不抑制Col 1、Col 3或α-SMA表达，但LC 3（shLC 3）敲低下调胶原表达。Adp 53调节的自噬改变了Bcl-2和Bcl-xL的表达，但AdLC 3只影响Bcl-xL的表达。沉默Bcl-xL抑制胶原蛋白的表达，但自噬也受到抑制。流式细胞术显示Bcl-2（sibcl-2）、Bcl-xL（sibcl-xL）和Adp 53的沉默显著增加了HSF中的凋亡。因此，wtp 53通过调节自噬性HSF凋亡来抑制HSF中的纤维化;此外，sibcl-xL对自噬的抑制具有抗纤维化作用。此外，用Adp 53、AdLC 3、shLC 3、sibcl-2和sibcl-xL处理减少了兔耳瘢痕模型中的瘢痕形成。这些数据证实了wtp 53调节的自噬和自噬性HSF凋亡可以作为HS治疗的潜在分子靶点。
Hypertrophic scarring is a serious fibrotic skin disease, and the abnormal activation of hypertrophic scar fibroblasts (HSFs) intensifies its pathogenesis. Our previous studies have demonstrated that the dysregulation of autophagy in HSFs is associated with fibrosis. However, knowledge regarding the regulation of HS fibrosis by p53-modulated autophagy is limited. Here, we investigated the effect of p53-modulated autophagy on HS fibrosis. The overexpression of wtp53 (Adp53) promoted autophagic capacity and inhibited collagen and α-SMA expression in HSFs. In contrast, LC3 (AdLC3) overexpression did not suppress Col 1, Col 3, or α-SMA expression, but LC3 (shLC3) knockdown downregulated collagen expression. Adp53-modulated autophagy altered Bcl-2 and Bcl-xL expression, but AdLC3 affected only Bcl-xL expression. Silencing Bcl-xL suppressed collagen expression, but autophagy was also inhibited. Flow cytometry showed that the silencing of Bcl-2 (sibcl-2), Bcl-xL (sibcl-xL), and Adp53 significantly increased apoptosis in the HSFs. Therefore, wtp53 inhibited fibrosis in the HSFs by modulating autophagic HSF apoptosis; moreover, the inhibition of autophagy by sibcl-xL had antifibrotic effects. In addition, treatment with Adp53, AdLC3, shLC3, sibcl-2, and sibcl-xL reduced scar formation in a rabbit ear scar model. These data confirm that wtp53-modulated autophagy and autophagic HSF apoptosis can serve as potential molecular targets for HS therapy.