CARD11 blockade suppresses murine collagen‐induced arthritis via inhibiting CARD11/Bcl10 assembly and T helper type 17 response
CARD11 blockade suppresses murine collagen‐induced arthritis via inhibiting CARD11/Bcl10 assembly and T helper type 17 response
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DOI：
10.1111/cei.12275
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发表时间：
2014-05
影响因子：
4.6
通讯作者：
H. Wang;J. Zhao;H. Zhang;Y. Huang;S. Wang;Q. Tu;N. Yang
中科院分区：
文献类型：
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作者：
H. Wang;J. Zhao;H. Zhang;Y. Huang;S. Wang;Q. Tu;N. Yang
支架蛋白caspase募集结构域蛋白11(CARD11)参与炎症和自身免疫的调节。本研究旨在探讨CARD11在类风湿关节炎(RA)发病机制中的作用。胶原性关节炎(CIA)小鼠在CIA建立后每隔3天给予CARD11靶向干扰RNA(CARD11 SiRNA)或对照siRNA腹腔注射治疗。每隔一天记录一次关节炎临床评分。滑膜炎症和软骨侵蚀通过组织学和微型计算机断层扫描(Micro-CT)评价。采用酶联免疫吸附试验(EL ISA)检测血清抗II型胶原抗体和细胞因子水平。免疫沉淀法和免疫印迹法检测CARD11/Bcl10的形成和核转录因子-kappaB(NF-κB)的活化，流式细胞仪检测辅助性T细胞(Th17)的百分率。全身应用CARD11 siRNA可显著降低CIA严重程度的临床评分。组织学显示，CARD11 siRNA治疗可减轻关节炎症和破坏。Micro-CT显示CARD11 siRNA处理组小鼠的关节破坏比对照组小鼠轻。CARD11siRNA处理后抑制了CARD11/Bcl10的形成和随后的NF-κB的激活。此外，经CARD11siRNA治疗后，致炎细胞因子IL-1β、IL-6和IL-17显著降低，血清抗CII抗体和Th1 7细胞百分率也显著降低。CARD11通过形成CARD11/Bcl10复合体和增强Th17细胞应答参与CIA的发病机制。靶向CARD11为RA治疗策略的发展提供了一个新的研究方向。
The scaffold protein caspase recruitment domain‐containing protein 11 (CARD11) is implicated in the regulation of inflammation and autoimmunity. The present study aimed to explore the role of CARD11 in the pathogenesis of rheumatoid arthritis (RA). Mice with collagen‐induced arthritis (CIA) were treated with either CARD11‐targeted interfering RNA (CARD11 siRNA) or control siRNA by intraperitoneal injection every 3 days after CIA establishment. The clinical score of arthritis was recorded every other day. Synovial inflammation and cartilage erosion were evaluated by histology and microcomputed tomography (micro‐CT). Serum anti‐type II collagen (anti‐CII) antibodies and cytokines were measured by enzyme‐linked immunosorbent assay (ELISA). The CARD11/Bcl10 formation and nuclear factor‐kappa B (NF‐κB) activation was assessed by immunoprecipitation and immunoblotting, and the percentage of T helper type 17 (Th17) cells was determined by flow cytometry. Systemic administration of CARD11 siRNA significantly reduced the clinical score of CIA severity. As indicated by the histology, joint inflammation and destruction were attenuated by CARD11 siRNA treatment. Micro‐CT demonstrated less severe joint destruction in CARD11 siRNA‐treated mice than in control mice. CARD11 siRNA treatment resulted in inhibition of CARD11/Bcl10 formation and the subsequent NF‐κB activation. In addition, treatment with CARD11 siRNA resulted in a pronounced decrease in proinflammatory cytokines interleukin (IL)‐1β, IL‐6 and IL‐17. Serum anti‐CII antibody and the percentage of Th17 cells were also significantly reduced. CARD11 is involved in the pathogenesis of CIA by formation of the CARD11/Bcl10 complex and enhancement of the Th17 cell response. Targeting CARD11 provides a novel research direction in the development of therapeutic strategies for RA.