Chitinase 3-Like 1 Promotes Endothelial-to-Mesenchymal Transition in Systemic Sclerosis via Mechanistic Target of Rapamycin Complex 1 Signaling Pathway.

Abstract

Systemic sclerosis (SSc) is a complicated autoimmune connective tissue disorder. Endothelial-to-mesenchymal transition (EndoMT) contributes to vasculopathy and fibrosis in SSc, yet its underlying mechanism remains to be elucidated. Here, we determined the role and mechanism of chitinase 3-like 1 (CHI3L1) in SSc EndoMT. Skin sections were immunostained for detecting the EndoMT and the expression pattern of CHI3L1 in patients with SSc. Human umbilical vein endothelial cells (HUVECs) were stimulated with recombinant CHI3L1 and anti-CHI3L1 antibody (CHI3L1 Ab) to explore the effects of CHI3L1 on ECs in vitro. In vivo, the bleomycin (BLM)-induced SSc mice were treated with CHI3L1 Ab to investigate the improvement of vasculopathy and fibrosis. Furthermore, proteomics was conducted to explore the specific mechanism by which CHI3L1 induces EndoMT in ECs. Immunofluorescence staining of skin sections confirmed EndoMT and the co-localization of CHI3L1 and ECs in patients with SSc. Subsequently, CHI3L1 was demonstrated to facilitate EndoMT in HUVECs. Furthermore, treatment with CHI3L1 Ab in BLM-SSc mice showed alleviation in SSc vasculopathy and fibrosis. Mechanistically, CHI3L1 mediated EndoMT primarily by binding to the CD44 receptor on ECs, then activating the downstream Akt/mechanistic target of rapamycin complex 1 (mTORC1)/S6 kinase signaling pathway, thereby regulating the EndoMT trigger transcription factors Snail and Slug. Finally, administration of rapamycin, an mTORC1 inhibitor, has been shown to inhibit the CHI3L1-mediated EndoMT process. This research reveals a new function of CHI3L1 in facilitating EndoMT in SSc and highlights CHI3L1 as a promising therapeutic target for SSc.