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Metabolomics-based identification of bioactive metabolites holds promise for enhancing the diagnosis, prevention, and treatment of rheumatoid arthritis (RA). Targeting specific cell populations with metabolite dysregulation presents novel opportunities for modulating disease progression in RA. The alteration of endogenous ligands is dynamic and cell type specific. Each endogenous ligand contributes a unique mode of metabolic-sensing G protein-coupled receptor (GPCR) activation. Metabolite-sensing GPCR signals originating from the synovial joint and gut have a regulatory role in RA-related inflammatory immune responses. Persistent inflammation in damaged joints results in metabolic dysregulation of the synovial microenvironment, causing pathogenic alteration of cell activity in rheumatoid arthritis (RA). Recently, the role of metabolite and metabolite-sensing G protein-coupled receptors (GPCRs) in the RA-related inflammatory immune response (IIR) has become a focus of research attention. These GPCRs participate in the progression of RA by modulating immune cell activation, migration, and inflammatory responses. Here, we discuss recent evidence implicating metabolic dysregulation in RA pathogenesis, focusing on the connection between RA-related IIR and GPCR signals originating from the synovial joint and gut. Furthermore, we discuss future directions for targeting metabolite-sensing GPCRs for therapeutic benefit, emphasizing the importance of identifying endogenous ligands and investigating the various transduction mechanisms involved. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease with a complex etiology. Monocyte-derived macrophages (MDMs) infiltration are associated with RA severity. We have reported the deletion of G-protein-coupled receptor kinase 2 (GRK2) reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor signaling. However, as more GRK2-interacting proteins were discovered, the GRK2 interactome mechanisms in RA have been understudied. Thus, in the collagen-induced arthritis mouse model, we performed genetic GRK2 deletion using GRK2 f/f Lyz2 -Cre+/− mice. Synovial inflammation and M1 polarization were improved in GRK2 f/f Lyz2 -Cre+/− mice. Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptor γ (PPAR γ) as a new GRK2-interacting protein. We further confirmed that fms-related tyrosine kinase 1 (Flt-1), which promoted macrophage migration to induce angiogenesis, was inhibited by GRK2-PPAR γ signaling. Mechanistically, excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPAR γ ligand-binding domain and enhanced Flt-1 transcription. Furthermore, the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology, Flt-1+ macrophages induced-synovial inflammation, and angiogenesis. Altogether, we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular signaling. Targeting GRK2 activity is a viable strategy to inhibit MDMs infiltration, affording a distinct way to control joint inflammation and angiogenesis of RA. The recruitment of GRK2 to the membrane inhibits PPAR γ -Tyr473 activation, consequently leading to synovial Flt-1+ macrophages infiltration, ultimately aggravating synovial inflammation and angiogenesis in rheumatoid arthritis. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Purpose: Abnormal kynurenine (Kyn) metabolism has been closely linked to the pathogenesis of rheumatoid arthritis (RA). The aims of this study were to investigate the role of tryptophan 2,3‐dioxygenase 2 (TDO2), a rate‐limiting enzyme that converts tryptophan (Trp) to Kyn, in regulating fibroblast‐like synoviocyte (FLS)‐mediated synovial inflammation in autoimmune arthritis. Experimental Approach The expression of TDO2 was determined by immunohistochemistry, confocal laser scanning fluorescence microscopy, imaging flow cytometry and Western blot. TDO2 activity was tested by HPLC and colorimetric assay. TDO2 siRNA and TDO2 inhibitor 680C91 were used to inhibit TDO2 in AA‐FLS function in vitro. A rat model of adjuvant‐induced arthritis (AA) was used to evaluate the in vivo effect of allopurinol (Allo), a TDO2 inhibitor. Key Results: TDO2 expression was strongly increased in synovial tissue and FLS of RA and AA. Immune cells were found to express high amount of TDO2 proteins at the peak stage of AA. Pharmacological inhibition or knockdown of TDO2 in AA‐FLS resulted in a reduced proliferation, secretion, migration and invasion. Kyn restored the inhibitory effect of TDO2 inhibition on activation of AA‐FLS. Allo treatment ameliorated the arthritis severity and decreased the activity of TDO2. Conclusion and Implications: Our results suggest that elevated TDO2 expression may contribute to synovial inflammation and joint destruction during arthritis. Therefore, targeting TDO2 activity and the Kyn pathway of Trp degradation may represent a potential therapeutic strategy in RA. [ABSTRACT FROM AUTHOR]

Macrophages maintain a dynamic balance in physiology. Various known or unknown microenvironmental signals influence the polarization, activation and death of macrophages, which creates an imbalance that leads to disease. Rheumatoid arthritis (RA) is characterized by the massive infiltration of a variety of chronic inflammatory cells in synovia. Abundant activated macrophages found in RA synovia are an early hallmark of RA, and the number of these macrophages can be decreased after effective treatment. In RA, the proportion of M1 (pro‐inflammatory macrophages) is higher than that of M2 (anti‐inflammatory macrophages). The increased pro‐inflammatory ability of macrophages is related to their excessive activation and proliferation as well as an enhanced anti‐apoptosis ability. At present, there are no clinical therapies specific to macrophages in RA. Understanding the mechanisms and functional consequences of the heterogeneity of macrophages will aid in confirming their potential role in inflammation development. This review will outline RA‐related macrophage properties (focus on polarization, metabolism and apoptosis) as well as the origin of macrophages. The molecular mechanisms that drive macrophage properties also be elucidated to identify novel therapeutic targets for RA and other autoimmune disease. [ABSTRACT FROM AUTHOR]

Inflammation, as a feature of rheumatoid arthritis (RA), leads to the activation of endothelial cells (ECs). Activated ECs induce atherosclerosis through an increased expression of leukocyte adhesion molecules. Endothelial dysfunction (ED) is recognized as a failure of endothelial repair mechanisms. It is also an early preclinical marker of atherosclerosis and is commonly found in RA patients. RA is now established as an independent cardiovascular risk factor, while mechanistic determinants of ED in RA are still poorly understood. An expanding body of study has shown that EC at a site of RA is both active participant and regulator of inflammatory process. Over the last decade, a role for endothelial dysfunction in RA associated with cardiovascular disease (CVD) has been hypothesized. At the same time, several maintenance drugs targeting this phenomenon have been tested, which has promising results. Assessment of endothelial function may be a useful tool to identify and monitor RA patients. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disease. Enhanced G protein coupled receptor kinase 2 (GRK2) translocation and prostaglandin E4 receptor (EP4) desensitization play a critical role in fibroblast-like synoviocytes (FLS) dysfunction. Paeoniflorin-6'O-benzene sulfonate (CP-25) exerts a protective effect in arthritis in the RA animal models. To demonstrate the role of Gβγ in EP4 desensitization and the mechanisms of CP-25 that protects FLS in RA, RA-FLS and adjuvant-induced arthritis (AA-FLS) were isolated from synovium of RA patients and AA rats. RA-FLS, AA-FLS and MH7A were treated with CP-25, Gβγ agonist and antagonist. The cell membrane expression of EP4, GRK2, and Gβγ were detected using western blot analysis. Co-immunoprecipitation (Co-IP) and immunofluorescence were adopted to detect the interactions of GRK2-Gβγ, GRK2-EP4, and EP4-Gβγ. Cell Counting Kit-8 and Transwell assay were used to analyze the proliferation and migration of the FLS. An increased membrane expression of GRK2 and Gβγ, enhanced GRK2-Gβγ interaction and decreased EP4 membrane expression in the RA synovial tissue were identified. In vitro, prostaglandin E2 (PGE2) enhanced the proliferation and migration of FLS. CP-25 exhibited an inhibition effect similar to Gβγ inhibitor, which downregulated GRK2-EP4 interaction, blocked the translocation of GRK2, and reversed EP4 desensitization, leading to the suppression of the proliferation and migration induced by PGE2. These results elucidated that an enhanced GRK2-Gβγ interaction was involved in the EP4 desensitization and dysfunction. CP-25 regulated EP4-GRK2-Gβγ signaling and re-sensitized EP4 by inhibiting GRK2-Gβγ interaction. The regulation of EP4-Gβγ-GRK2 signaling may be a novel potential therapeutic target in RA. [ABSTRACT FROM AUTHOR]

• ECM imbalance plays an important role in arthritis disease and is an effective intervention. • ECM affects synovium mainly through its components and related signaling pathways. • ECM in synovium offers promise for the treatment and prevention of arthritis. Extracellular matrix (ECM) is a three-dimensional network entity composed of extracellular macromolecules. ECM in synovium not only supports the structural integrity of synovium, but also plays a crucial role in regulating homeostasis and damage repair response in synovium. Obvious disorders in the composition, behavior and function of synovial ECM will lead to the occurrence and development of arthritis diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and psoriatic arthritis (PsA). Based on the importance of synovial ECM, targeted regulation of the composition and structure of ECM is considered to be an effective measure for the treatment of arthritis disease. This paper reviews the current research status of synovial ECM biology, discusses the role and mechanism of synovial ECM in physiological status and arthritis disease, and summarizes the current strategies for targeting synovial ECM to provide information for the pathogenesis, diagnosis and treatment of arthritis disease. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the expression and effects of B-lymphocyte stimulator (BLyS) in T cell-mediated autoimmune arthritis, a rat model of human rheumatoid arthritis (RA). Rat adjuvant-induced arthritis (AA) was induced by intradermal injection of 0.1 ml complete Freund's adjuvant. Arthritis was evaluated by the histopathological examination of joint ankle. The BLyS expression was detected by immunohistochemical analysis. The level of BLyS and interleukin (IL)-17 were assayed by enzyme-linked immunosorbent assay. The gene expression of BLyS and its receptors (TACI, BCMA and BAFF-R) were assessed by quantitative reverse-transcription polymerase chain reaction. The effect of BLyS on the function of T cell was investigated by transwell assay. Using an AA rat model, we detected dysregulated expression and level of BLyS and its receptors in the local joint synovium tissue, peripheral lymphoid organs (spleen) and immune cells (macrophage, dendritic cells (DC) and T cell) at the peak of inflammation. In vitro, BLyS-treated DC induced IL-17 producing T cells. Neutralization of BLyS by the TACI-Ig fusion protein attenuated these stimulating effects of BLyS. These data suggest that the overproduction of BLyS may contribute to T cell responses and may be an attractive target for control of autoimmune diseases, such as RA, that involves both T and B cells. [ABSTRACT FROM AUTHOR]