Bile Acids Elevated in Chronic Periaortitis Could Activate Farnesoid-X-Receptor to Suppress IL-6 Production by Macrophages

被引:15
作者
Cao, Shan [1 ]
Meng, Xinyu [1 ]
Li, Yixuan [1 ]
Sun, Li [2 ]
Jiang, Lindi [3 ]
Xuan, Hanqing [4 ]
Chen, Xiaoxiang [1 ]
机构
[1] Shanghai Jiao Tong Univ, Ren Ji Hosp, Dept Rheumatol, Sch Med, Shanghai, Peoples R China
[2] Wenzhou Med Univ, Dept Rheumatol, Affiliated Hosp 1, Wenzhou, Peoples R China
[3] Fudan Univ, Zhongshan Hosp, Dept Rheumatol, Shanghai, Peoples R China
[4] Shanghai Jiao Tong Univ, Ren Ji Hosp, Dept Urol, Sch Med, Shanghai, Peoples R China
来源
FRONTIERS IN IMMUNOLOGY | 2021年 / 12卷
基金
美国国家科学基金会;
关键词
bile acid; farnesoid-x-receptor; IL-6; chronic periaortitis; macrophages; EFFICACY;
D O I
10.3389/fimmu.2021.632864
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Chronic periaortitis (CP) is a rare autoimmune disease without effective treatment. By analyzing the serum bile acid spectrum in 28 CP patients with the ultra-performance liquid chromatography-tandem mass spectrometry, we found that the bile acids were significantly altered in CP patients, with significant increases in chenodeoxycholic acid (CDCA) and glycochenodeoxycholic acid (GCDCA) and decrease in deoxycholic acid (DCA). Signaling pathway enrichment analysis from the RNA sequencing results suggested that the altered gene sets in PBMC of CP patients were associated with bile acid metabolism. Furthermore, we found that pathological concentration of CDCA could significantly inhibited IL-6 expression in RAW 264.7 cells after LPS stimulation. Since CDCA is a well-known natural high-affinity ligand for the bile acid receptor farnesoid-x-receptor (FXR) while GW4064 is the synthetic specific agonist of this receptor, we then revealed that GW4064 significantly decreased IL-6 expression in RAW 264.7 cells and bone marrow-derived macrophages but not in FXR-/- macrophages upon LPS stimulation. The western blot results with the anti-FXR antibody showed significantly increased expression in the nuclear proportion, suggesting that FXR agonist promoted the transportation of FXR into the nucleus but did not increase the FXR expression in macrophages. Dual-luciferase report assay and ChIP assay demonstrated that upon activation, FXR could directly bind to the promoter site of IL-6, leading to the decreased expression of IL-6. Thus, bile acids, especially CDCA, may operate to damp inflammation via FXR-mediated downregulation of IL-6 in mononuclear cells and provide a protective mechanism for CP patients.
引用
收藏
页数:12
相关论文
共 27 条
  • [1] Methotrexate plus prednisone in patients with relapsing idiopathic retroperitoneal fibrosis
    Alberici, Federico
    Palmisano, Alessandra
    Urban, Maria L.
    Maritati, Federica
    Oliva, Elena
    Manenti, Lucio
    Ferretti, Stefania
    Cobelli, Rocco
    Buzio, Carlo
    Vaglio, Augusto
    [J]. ANNALS OF THE RHEUMATIC DISEASES, 2013, 72 (09) : 1584 - 1586
  • [2] Cyclophosphamide is a highly effective and safe induction therapy in chronic periaortitis: a long-term follow-up of 35 patients with chronic periaortitis
    Binder, M.
    Uhl, M.
    Wiech, T.
    Kollert, F.
    Thiel, J.
    Sass, J. O.
    Walker, U. A.
    Peter, H. H.
    Warnatz, K.
    [J]. ANNALS OF THE RHEUMATIC DISEASES, 2012, 71 (02) : 311 - 312
  • [3] BRUUSGAARD A, 1976, LANCET, V1, P700
  • [4] Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR
    Calkin, Anna C.
    Tontonoz, Peter
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2012, 13 (04) : 213 - 224
  • [5] IMMUNOSUPPRESSIVE PROPERTIES OF CHENODEOXYCHOLIC AND URSODEOXYCHOLIC ACIDS IN THE MOUSE
    CALMUS, Y
    WEILL, B
    OZIER, Y
    CHEREAU, C
    HOUSSIN, D
    POUPON, R
    [J]. GASTROENTEROLOGY, 1992, 103 (02) : 617 - 621
  • [6] Catanoso MG, 2012, CLIN EXP RHEUMATOL, V30, P776
  • [7] De Magalhaes Filho C Daniel, 2016, Cell, V166, P789, DOI 10.1016/j.cell.2016.08.001
  • [8] Bile Acids Activated Receptors Regulate innate immunity
    Fiorucci, Stefano
    Biagioli, Michele
    Zampella, Angela
    Distrutti, Eleonora
    [J]. FRONTIERS IN IMMUNOLOGY, 2018, 9
  • [9] New Therapeutic Targets in Autoimmune Cholangiopathies
    Gerussi, Alessio
    Luca, Martina
    Cristoferi, Laura
    Ronca, Vincenzo
    Mancuso, Clara
    Milani, Chiara
    D'Amato, Daphne
    O'Donnell, Sarah Elizabeth
    Carbone, Marco
    Invernizzi, Pietro
    [J]. FRONTIERS IN MEDICINE, 2020, 7
  • [10] Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome
    Guo, Chuansheng
    Xie, Shujun
    Chi, Zhexu
    Zhang, Jinhua
    Liu, Yangyang
    Zhang, Li
    Zheng, Mingzhu
    Zhang, Xue
    Xia, Dajing
    Ke, Yuehai
    Lu, Linrong
    Wang, Di
    [J]. IMMUNITY, 2016, 45 (04) : 802 - 816