Elsevier

Laboratory Investigation

Volume 98, Issue 11, November 2018, Pages 1423-1437
Laboratory Investigation

Article
Wild-type p53-modulated autophagy and autophagic fibroblast apoptosis inhibit hypertrophic scar formation

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Abstract

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.

The dysregulation of dermal fibroblast proliferation and apoptosis is thought to be related to hypertrophic scar formation. In this study, the authors show that the balance of autophagy in HSF is critical for fibrosis formation, and both downregulation and excessive upregulation of autophagy inhibits collagen expression via wild type p53 and the pro-survival protein Bcl-xL.

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These authors contributed equally: Jihong Shi, Houan Xiao, Jun Li.