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Autophagy protein LC3 regulates the fibrosis of hypertrophic scar by controlling Bcl-xL in dermal fibroblasts.


PMID 29212187

Abstract

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.

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