Optineurin restrains CCR7 degradation to guide type II collagen-stimulated dendritic cell migration in rheumatoid arthritis.

Wenxiang HONG; Hongbo MA; Zhaoxu YANG; Jiaying WANG; Bowen PENG; Longling WANG; Yiwen DU; Lijun YANG; Lijiang ZHANG; Zhibin LI; Han HUANG; Difeng ZHU; Bo YANG; Qiaojun HE; Jiajia WANG; Qinjie WENG

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Optineurin restrains CCR7 degradation to guide type II collagen-stimulated dendritic cell migration in rheumatoid arthritis.

Author: Wenxiang HONG ¹ ; Hongbo MA ¹ ; Zhaoxu YANG ¹ ; Jiaying WANG ¹ ; Bowen PENG ¹ ; Longling WANG ¹ ; Yiwen DU ¹ ; Lijun YANG ¹ ; Lijiang ZHANG ² ; Zhibin LI ¹ ; Han HUANG ¹ ; Difeng ZHU ¹ ; Bo YANG ¹ ; Qiaojun HE ¹ ; Jiajia WANG ¹ ; Qinjie WENG ¹
Author Information

1. Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
2. Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou 310059, China.
Publication Type:Journal Article
Keywords: CCR7; Degradation; Dendritic cells; Migration; Optineurin; Rheumatoid arthritis; Saikosaponin D; Type II collagen
From: Acta Pharmaceutica Sinica B 2025;15(3):1626-1642
CountryChina
Language:English
Abstract: Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn-deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.