Activation of TGR5 alleviates inflammation in rheumatoid arthritis peripheral blood mononuclear cells and in mice with collagen II‑induced arthritis

Abstract

Rheumatoid arthritis (RA) is characterized by chronic inflammatory synovitis resulting in progressive joint destruction. Persistent synovial inflammation is induced by activation of various inflammatory cells. G-protein-coupled bile acid receptor 1 (TGR5) is a G-protein-coupled receptor activated by various bile acids, which has been reported to act as a key adaptor in regulating various signaling pathways involved in inflammatory responses and a diverse array of physiological processes, including bile acid synthesis, lipid and carbohydrate metabolism, carcinogenesis, immunity and inflammation. In the present study, TGR5 expression was detected in RA peripheral blood mononuclear cells (PBMCs), and its association with clinical disease activity, histological synovitis severity and radiological joint destruction was analyzed. Subsequently, the role and potential underlying mechanisms of TGR5 in the PBMCs of patients with RA and mice with collagen II-induced arthritis (CIA) were investigated. PBMCs were obtained from 50 patients with RA and 40 healthy controls (HCs). The mRNA and protein expression levels of TGR5 were detected in PBMCs via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence staining, respectively. Additionally, the levels of proinflammatory cytokines were analyzed by RT-qPCR and enzyme-linked immunosorbent assay (ELISA). The activation of nuclear factor-κB (NF-κB) and IκB kinase a was determined via western blot analysis. The anti-arthritic and anti-inflammatory effects of LCA on mice with CIA were then investigated. The arthritis score was assessed, and the protein levels of proinflammatory cytokines in the plasma of mice were detected via ELISA. TGR5 mRNA expression was significantly downregulated in the PBMCs of patients with RA compared with in those of the HCs (0.53±0.58 for patients vs. 1.49±0.83 for HCs; P<0.001); similar findings were observed at the protein level. The mRNA expression levels of TGR5 in the PBMCs of patients with RA with a high 28-Joint Disease Activity Score (DAS28) were significantly decreased compared with in patients with a low DAS28 (0.81±0.65 for low score vs. 0.35±0.46 for high score; P=0.002). Furthermore, TGR5 expression was significantly correlated with the levels of C-reactive protein (r=−0.429; P=0.002) and the DAS28 (r=−0.383; P=0.006). RT-qPCR and ELISA analyses indicated that lithocholic acid (LCA, 10 mg/kg/day) attenuated lipopolysaccharide-induced proinflammatory cytokine production via inhibition of NF-κB activity in the PBMCs of patients with RA. In addition, the arthritis score was significantly decreased in LCA-treated CIA mice compared with in non-treated CIA mice. The increased production of tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and IL-8 was significantly reduced in the plasma of LCA-treated CIA mice compared with the control. In conclusion, TGR5 may contribute to the inflammation of PBMCs in patients with RA and mice with CIA.

Dysregulation of Bile Acids, Lipids, and Nucleotides in Psoriatic Arthritis Revealed by Unbiased Profiling of Serum Metabolites

“…Based on the observation that rheumatoid arthritis (RA) improved in patients with jaundice (37), RA patients were treated with a short course of intravenous bile acids and experienced significant short‐term improvement in arthritis, but treatment was complicated by development of phlebitis (38). In a subsequent study, expression of the TGR5 bile acid receptor was significantly lower in RA peripheral blood mononuclear cells compared to healthy controls, and levels correlated inversely with the Disease Activity Score in 28 joints outcome measure (30). In preclinical models, therapy with a secondary bile acid, lithocholic acid, significantly lessened joint inflammation in the collagen‐induced arthritis (CIA) model (30), and bile acid treatment suppressed development of psoriasis lesions in the IL‐23 minicircle model via inhibition of RORγt and CCL20 expression (39).…”

“…Both primary and secondary bile acids activate nuclear and plasma membrane receptors including farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (TGR5) expressed on macrophages, dendritic cells, and natural killer T cells (29). Engagement of these receptors by bile acids promote an antiinflammatory response through the suppression of tumor necrosis factor (TNF), interleukin-6 (IL-6), and IL-8 and by inhibition of the NF-κB transcription factor (30). Secondary bile acids suppress Th17 cell differentiation by direct suppression of RAR-related orphan receptor γt (RORγt) and enhance the differentiation of CD4+ lymphocytes to FoxP3+ Treg cells (31,32).…”

The bridge of the gut–joint axis: Gut microbial metabolites in rheumatoid arthritis

“…Elevated levels of primary BAs have been found in the faeces of some RA patients, indicating their potential to predict RA arthritis severity ( 23 – 25 ). Increased bile acid in RA patients andmice has been shown to reduce the number of swollen andtender joints, erythrocyte sedimentation rate (ESR) ( 26 ), Creactiveprotein (CRP) ( 27 ), anti-CCP antibodies RF-IgM, RFIgGand RF-IgA ( 28 ). Primary BAs, such as cholic acid (CA) and chenodeoxycholic acid (CDCA), are synthesized from cholesterol in the liver and can be accomplished by two different pathways ( 29 ).…”

“Osteomicrobiology”: The Nexus Between Bone and Bugs

“…Expression of Tgr5 was found to be negatively correlated with disease severity. On the other hand, treatment with lithocholic acid has been reported to decrease arthritis score in collagen II-induced arthritis mouse model along with suppressing inflammatory responses in RA patients ( Li Z. et al, 2019 ). Zhao et al reported that bile acids are positively correlated with BMD as osteoporotic and osteopenic post-menopausal women have significantly reduced levels of bile acids than healthy controls ( Zhao et al, 2020 ).…”