Frontiers in Pharmacology (Jun 2023)
HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome
- Junhao Yin,
- Junhao Yin,
- Junhao Yin,
- Junhao Yin,
- Jiabao Xu,
- Jiabao Xu,
- Jiabao Xu,
- Jiabao Xu,
- Changyu Chen,
- Changyu Chen,
- Changyu Chen,
- Changyu Chen,
- Xinyi Ma,
- Xinyi Ma,
- Xinyi Ma,
- Xinyi Ma,
- Hanyi Zhu,
- Hanyi Zhu,
- Hanyi Zhu,
- Hanyi Zhu,
- Lisong Xie,
- Lisong Xie,
- Lisong Xie,
- Lisong Xie,
- Baoli Wang,
- Baoli Wang,
- Baoli Wang,
- Baoli Wang,
- Yanxiong Shao,
- Yanxiong Shao,
- Yanxiong Shao,
- Yanxiong Shao,
- Yijie Zhao,
- Yu Wei,
- Anni Hu,
- Zhanglong Zheng,
- Chuangqi Yu,
- Chuangqi Yu,
- Chuangqi Yu,
- Chuangqi Yu,
- Jiayao Fu,
- Jiayao Fu,
- Jiayao Fu,
- Jiayao Fu,
- Lingyan Zheng,
- Lingyan Zheng,
- Lingyan Zheng,
- Lingyan Zheng
Affiliations
- Junhao Yin
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- Junhao Yin
- National Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, China
- Junhao Yin
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Junhao Yin
- Shanghai Institute of Stomatology, Shanghai, China
- Jiabao Xu
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- Jiabao Xu
- National Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, China
- Jiabao Xu
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Jiabao Xu
- Shanghai Institute of Stomatology, Shanghai, China
- Changyu Chen
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- Changyu Chen
- National Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, China
- Changyu Chen
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Changyu Chen
- Shanghai Institute of Stomatology, Shanghai, China
- Xinyi Ma
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- Xinyi Ma
- National Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, China
- Xinyi Ma
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Xinyi Ma
- Shanghai Institute of Stomatology, Shanghai, China
- Hanyi Zhu
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- Hanyi Zhu
- National Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, China
- Hanyi Zhu
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Hanyi Zhu
- Shanghai Institute of Stomatology, Shanghai, China
- Lisong Xie
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- Lisong Xie
- National Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, China
- Lisong Xie
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Lisong Xie
- Shanghai Institute of Stomatology, Shanghai, China
- Baoli Wang
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- Baoli Wang
- National Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, China
- Baoli Wang
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Baoli Wang
- Shanghai Institute of Stomatology, Shanghai, China
- Yanxiong Shao
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- Yanxiong Shao
- National Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, China
- Yanxiong Shao
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Yanxiong Shao
- Shanghai Institute of Stomatology, Shanghai, China
- Yijie Zhao
- Department of Oral and Maxillofacial Surgery, Shanghai Stomatological Hospital, Fudan University, Shanghai, China
- Yu Wei
- Department of Oral and Maxillofacial Surgery, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School and Hospital of Stomatology, Tongji University, Shanghai, China
- Anni Hu
- Department of Oral and Maxillofacial Surgery, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School and Hospital of Stomatology, Tongji University, Shanghai, China
- Zhanglong Zheng
- Department of Oral and Maxillofacial Surgery, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School and Hospital of Stomatology, Tongji University, Shanghai, China
- Chuangqi Yu
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- Chuangqi Yu
- National Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, China
- Chuangqi Yu
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Chuangqi Yu
- Shanghai Institute of Stomatology, Shanghai, China
- Jiayao Fu
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- Jiayao Fu
- National Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, China
- Jiayao Fu
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Jiayao Fu
- Shanghai Institute of Stomatology, Shanghai, China
- Lingyan Zheng
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- Lingyan Zheng
- National Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, China
- Lingyan Zheng
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Lingyan Zheng
- Shanghai Institute of Stomatology, Shanghai, China
- DOI
- https://doi.org/10.3389/fphar.2023.1191692
- Journal volume & issue
-
Vol. 14
Abstract
Introduction: Sjögren’s syndrome (SS) is a chronic autoimmune disorder characterized by exocrine gland dysfunction, leading to loss of salivary function. Histological analysis of salivary glands from SS patients reveals a high infiltration of immune cells, particularly activated CD4+ T cells. Thus, interventions targeting abnormal activation of CD4+ T cells may provide promising therapeutic strategies for SS. Here, we demonstrate that Hect, uba, and wwe domain containing 1 (HUWE1), a member of the eukaryotic Hect E3 ubiquitin ligase family, plays a critical role in CD4+ T-cell activation and SS pathophysiology.Methods: In the context of HUWE1 inhibition, we investigated the impact of the HUWE1 inhibitor BI8626 and sh-Huwe1 on CD4+ T cells in mice, focusing on the assessment of activation levels, proliferation capacity, and cholesterol abundance. Furthermore, we examined the therapeutic potential of BI8626 in NOD/ShiLtj mice and evaluated its efficacy as a treatment strategy.Results: Inhibition of HUWE1 reduces ABCA1 ubiquitination and promotes cholesterol efflux, decreasing intracellular cholesterol and reducing the expression of phosphorylated ZAP-70, CD25, and other activation markers, culminating in the suppressed proliferation of CD4+ T cells. Moreover, pharmacological inhibition of HUWE1 significantly reduces CD4+ T-cell infiltration in the submandibular glands and improves salivary flow rate in NOD/ShiLtj mice.Conclusion: These findings suggest that HUWE1 may regulate CD4+ T-cell activation and SS development by modulating ABCA1-mediated cholesterol efflux and presents a promising target for SS treatment.
Keywords
