p75NTR silencing inhibits proliferation, migration, and extracellular matrix deposition of hypertrophic scar fibroblasts by activating autophagy through inhibiting the PI3K/Akt/mTOR pathway

Abstract

Hypertrophic scar (HS) results from abnormal wound healing, accompanied by excessive hypercellularity, migration, and extracellular matrix (ECM) deposition. Autophagy dysregulation plays crucial roles during HS formation. The overexpressed p75 neurotrophin receptor (p75NTR) in injured skin tissue after wound healing becomes a factor aggravating scar. This study was designed to investigate the role of p75NTR and p75NTR-mediated autophagy in the process of HS. The results revealed that p75NTR expression was significantly upregulated while that of autophagy proteins was downregulated in cicatrix at 3 and 6 months after a burn, which was recovered at 12 months. p75NTR silencing inhibited proliferation, migration, and ECM deposition of hypertrophic scar fibroblasts (HSF), whereas p75NTR overexpression presented the opposite results. Silencing of p75NTR reduced the expression of PI3K/Akt/mTOR signaling molecules while enhancing that of autophagy proteins. Importantly, PI3K agonist (IGF-1) intervention notably decreased the levels of LC3B II/I and Beclin-1 and restored the inhibitory effects of p75NTR silencing on proliferation, migration, and ECM deposition of HSF. Concurrently, autophagy inhibitor 3-methyladenine (3-MA) treatment exhibited the same variation trends with IGF-1. Taken together, these findings demonstrated that p75NTR silencing inhibits proliferation, migration, and ECM deposition of HSF by activating autophagy by inhibiting the PI3K/Akt/mTOR pathway.