Full Papers
Endoplasmic reticulum stress perpetuated toll-like receptor signalling-mediated inflammation in rheumatoid arthritis via X-box-binding protein-1
F. Hu1, Y. Tang2, P. Wang3, M. Bai4, X. Li5, J. Song6, L. Shi7, X. Sun8, M. Jin9, Z. Li10, X. Li11
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, and State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. fanleihu@bjmu.edu.cn
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Liaoning, China.
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, and Peking-Tsinghua Center for Life Sciences, Beijing, China.
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, and Peking-Tsinghua Center for Life Sciences, Beijing, China.
- Department of Rheumatology and Immunology, Peking University International Hospital, Beijing, China.
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Liaoning, China.
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Liaoning, China.
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, and Peking-Tsinghua Center for Life Sciences, Beijing, China. li99@bjmu.edu.cn
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Liaoning, China. lixia416@163.com
CER13021
2021 Vol.39, N°4
PI 0859, PF 0867
Full Papers
PMID: 32896245 [PubMed]
Received: 16/12/2019
Accepted : 20/07/2020
In Press: 08/09/2020
Published: 08/07/2021
Abstract
OBJECTIVES:
Multiple physiological and pathological conditions interfere with the function of the endoplasmic reticulum (ER). However, much remains unknown regarding the impact of ER stress on toll-like receptors (TLRs) -induced inflammatory responses in rheumatoid arthritis (RA). The aim of this study was to reveal the effects of ER stress and its regulator, X-box-binding protein-1 (XBP-1), on the inflammatory response of RA synovial fibroblasts (RASF) to different TLRs ligands.
METHODS:
ER stress was induced in RASF by incubating with thapsigargin (Tg). TLR2 ligand Pam3CSK4, TLR3 ligand PolyIC, TLR4 ligand LPS were used to stimulate the cells. Effects of ER stress on TLRs-induced inflammatory mediators were determined by using RT-PCR, qPCR and ELISA analysis. Western blots analysis was used to detected the signalling pathways in this process. For gene silencing experiment, control scrambled or XBP-1 specific siRNA were transfected into RASF. T helper (Th)1/Th17 cells expansion was determined by flow cytometry analysis, and IFN-γ/IL-17A production in supernatants were collected for ELISA assay.
RESULTS:
ER stress potentiated the expression of inflammatory cytokines, MMPs and VEGF in RASF stimulated by different TLRs ligands, which was companied with enhanced the activation of NF-κB and MAPKs signalling pathways. Silencing XBP-1 in RASF could dampen TLRs signalling-simulated inflammatory response under ER stress. Moreover, blockade of XBP-1 reduced the generation of Th1 and Th17 cells mediated by RASF, and suppressed the production of IFN-γ and IL-17A.
CONCLUSIONS:
Our findings suggest that ER stress and XBP-1 may function in conjunction with TLRs to drive the inflammation of RASF, and this pathway may serve as a therapeutic target for the disease.
