CILP2 promotes hypertrophic scar through Snail acetylation by interaction with ACLY

Jianzhang Wang; Juan Du; Yuanyong Wang; Yajuan Song; Junzheng Wu; Tong Wang; Zhou Yu; Baoqiang Song

doi:10.1016/j.bbadis.2024.167202

CILP2 promotes hypertrophic scar through Snail acetylation by interaction with ACLY

Biochim Biophys Acta Mol Basis Dis. 2024 Apr 24;1870(5):167202. doi: 10.1016/j.bbadis.2024.167202. Online ahead of print.

Authors

Jianzhang Wang¹, Juan Du², Yuanyong Wang³, Yajuan Song¹, Junzheng Wu¹, Tong Wang¹, Zhou Yu⁴, Baoqiang Song⁵

Affiliations

¹ Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
² Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
³ Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China.
⁴ Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: yz20080512@163.com.
⁵ Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: songbq@fmmu.edu.cn.

PMID: 38670440
DOI: 10.1016/j.bbadis.2024.167202

Abstract

Background & aims: Hypertrophic scar (HS) is a skin fibroproliferative disorder occurring after burns, surgeries or traumatic injuries, and it has caused a tremendous economic and medical burden. Its molecular mechanism is associated with the abnormal proliferation and transition of fibroblasts and excessive deposition of extracellular matrix. Cartilage intermediate layer protein 2 (CILP2), highly homologous to cartilage intermediate layer protein 1 (CILP1), is mainly secreted predominantly from chondrocytes in the middle/deeper layers of articular cartilage. Recent reports indicate that CILP2 is involved in the development of fibrotic diseases. We investigated the role of CILP2 in the progression of HS.

Methods and results: It was found in this study that CILP2 expression was significantly higher in HS than in normal skin, especially in myofibroblasts. In a clinical cohort, we discovered that CILP2 was more abundant in the serum of patients with HS, especially in the early stage of HS. In vitro studies indicated that knockdown of CILP2 suppressed proliferation, migration, myofibroblast activation and collagen synthesis of hypertrophic scar fibroblasts (HSFs). Further, we revealed that CILP2 interacts with ATP citrate lyase (ACLY), in which CILP2 stabilizes the expression of ACLY by reducing the ubiquitination of ACLY, therefore prompting Snail acetylation and avoiding reduced expression of Snail. In vivo studies indicated that knockdown of CILP2 or ACLY inhibitor, SB-204990, significantly alleviated HS formation.

Conclusion: CILP2 exerts a vital role in hypertrophic scar formation and might be a detectable biomarker reflecting the progression of hypertrophic scar and a therapeutic target for hypertrophic scar.

Keywords: ACLY; CILP2; Fibroblasts; Hypertrophic scar; Snail.