{"title":"几丁质酶3-Like 1通过mTORC1信号通路促进系统性硬化症的内皮向间质转化。","authors":"Xiuyuan Wang,Xue Han,Jia Yu,Feifei Hu,Chengjie Huang,Cheng Chen,Liuting Huang,Ying Jiang,Xinzhi Xu,Manna Lin,Junxia Huang,Tianbao Ye,Ji Yang","doi":"10.1002/art.43356","DOIUrl":null,"url":null,"abstract":"OBJECTIVE\r\nSystemic 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.\r\n\r\nMETHODS\r\nSkin 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 endothelial cells (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.\r\n\r\nRESULTS\r\nImmunofluorescence 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/mTOR complex 1 (mTORC1)/S6K signaling pathway, thereby regulating the EndoMT trigger transcription factors Snail and Slug. Finally, administration of rapamycin, a mTORC1 inhibitor, has been shown to inhibit the CHI3L1 mediated EndoMT process.\r\n\r\nCONCLUSION\r\nThis research reveals a new function of CHI3L1 in facilitating EndoMT in SSc and highlight CHI3L1 as a promising therapeutic target for SSc.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"36 1","pages":""},"PeriodicalIF":10.9000,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Chitinase 3-Like 1 Promotes Endothelial-to-Mesenchymal Transition in Systemic Sclerosis via mTORC1 Signaling Pathway.\",\"authors\":\"Xiuyuan Wang,Xue Han,Jia Yu,Feifei Hu,Chengjie Huang,Cheng Chen,Liuting Huang,Ying Jiang,Xinzhi Xu,Manna Lin,Junxia Huang,Tianbao Ye,Ji Yang\",\"doi\":\"10.1002/art.43356\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"OBJECTIVE\\r\\nSystemic 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.\\r\\n\\r\\nMETHODS\\r\\nSkin 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 endothelial cells (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.\\r\\n\\r\\nRESULTS\\r\\nImmunofluorescence 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/mTOR complex 1 (mTORC1)/S6K signaling pathway, thereby regulating the EndoMT trigger transcription factors Snail and Slug. Finally, administration of rapamycin, a mTORC1 inhibitor, has been shown to inhibit the CHI3L1 mediated EndoMT process.\\r\\n\\r\\nCONCLUSION\\r\\nThis research reveals a new function of CHI3L1 in facilitating EndoMT in SSc and highlight CHI3L1 as a promising therapeutic target for SSc.\",\"PeriodicalId\":129,\"journal\":{\"name\":\"Arthritis & Rheumatology\",\"volume\":\"36 1\",\"pages\":\"\"},\"PeriodicalIF\":10.9000,\"publicationDate\":\"2025-08-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Arthritis & Rheumatology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/art.43356\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arthritis & Rheumatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/art.43356","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
Chitinase 3-Like 1 Promotes Endothelial-to-Mesenchymal Transition in Systemic Sclerosis via mTORC1 Signaling Pathway.
OBJECTIVE
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.
METHODS
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 endothelial cells (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.
RESULTS
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/mTOR complex 1 (mTORC1)/S6K signaling pathway, thereby regulating the EndoMT trigger transcription factors Snail and Slug. Finally, administration of rapamycin, a mTORC1 inhibitor, has been shown to inhibit the CHI3L1 mediated EndoMT process.
CONCLUSION
This research reveals a new function of CHI3L1 in facilitating EndoMT in SSc and highlight CHI3L1 as a promising therapeutic target for SSc.
期刊介绍:
Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.