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  2. Up-regulated DERL3 in fibroblast-like synoviocytes exacerbates inflammation of rheumatoid arthritis

Up-regulated DERL3 in fibroblast-like synoviocytes exacerbates inflammation of rheumatoid arthritis

  • Clin Immunol. 2020 Nov;220:108579. doi: 10.1016/j.clim.2020.108579.
Manman Geng 1 Ke Xu 2 Liesu Meng 1 Jing Xu 3 Congshan Jiang 3 Yuanxu Guo 3 Xiaoyu Ren 2 Xiaowei Li 3 Yizhao Peng 3 Si Wang 3 Fumeng Huang 3 Jing Zhang 3 Xipeng Wang 3 Wenhua Zhu 4 Shemin Lu 5
Affiliations

Affiliations

  • 1 Institute of Molecular and Translational Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, China.
  • 2 Xi'an Hong Hui Hospital, the Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, China.
  • 3 Institute of Molecular and Translational Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
  • 4 Institute of Molecular and Translational Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, China. Electronic address: zhuwenhua@xjtu.edu.cn.
  • 5 Institute of Molecular and Translational Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, China. Electronic address: lushemin@xjtu.edu.cn.
Abstract

Endoplasmic reticulum (ER) stress associated proteins contribute to the pathogenesis of rheumatoid arthritis (RA) through affecting synoviocyte proliferation and proinflammatory cytokine production. The role of DERL3, an ER-associated degradation component, in joint inflammation of RA was explored. Synovial tissues from RA and osteoarthritis (OA) patients were collected, and in RA synovial tissue, DERL3 showed up-regulation and significantly positive correlation with the expression of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-1. Immunofluorescence result suggested DERL3 was located in fibroblast-like synoviocytes (FLS). Among different inflammatory stimuli, DERL3 could be up-regulated by TNF-α stimulation in FLS. Under TNF-α stimulation, knocking down DERL3, the expression of IL-6, IL-8, MMP-1, MMP-13 was reduced and the activation of nuclear factor kappa B (NF-κB) signaling pathway was inhibited. In pristane-induced arthritis (PIA) rat model, Derl3 was up-regulated in synovial tissue and disease was attenuated after intraarticular injection of siDerl3. Overall, we conclude that TNF-α inducing DERL3 expression promotes the inflammation of FLS through activation of NF-κB signaling pathway, suggesting DERL3 plays important roles in the pathogenesis of RA and is a promising therapeutic target.

Keywords

DERL3; Fibroblast-like synoviocytes; PIA; Rheumatoid arthritis; TNF-α.

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