Irisin mitigates rheumatoid arthritis by suppressing mitochondrial fission via inhibiting YAP-Drp1 signaling pathway.

BACKGROUND: Irisin is a hormone-like factor secreted by muscle cells and produced by cleavage of the membrane protein fibronectin type III domain protein 5 (FNDC5), which exerts anti-inflammatory and anti-proliferative effects. However, the effects and the underlying mechanisms of irisin in rheumatoid arthritis (RA) are still unclear. METHOD: Collagen-induced arthritis (CIA) model was induced in DBA/1 mice and then treated with irisin. Arthritis index, paw thickness, weight, number of affected paws, serum inflammatory factors and related pathological tests were measured. RA fibroblast-like synoviocytes (RA-FLSs) were pretreated with IL-1ß and irisin, and the migration, proliferation, invasion, oxidative stress and mitochondrial related function of RA-FLSs were detected. RESULTS: Irisin significantly improved arthritis symptoms in CIA mice, as indicated by reduced arthritis index, alleviated paw thickness, decreased the number of affected paws and inhibited release of inflammatory factors. Irisin alleviated joint destruction, FLSs proliferation and the expression of YES-associated protein (YAP) and mitochondrial dynamic related protein 1 (Drp1) in the FLSs of CIA mice. In vitro experiment, irisin inhibited the proliferation, migration and invasion of RA-FLSs and improved oxidative stress induced by IL-1ß, thereby restraining the pathogenic transformation of RA-FLSs. Mechanically, irisin suppressed the nuclear translocation of YAP, in turn, could reduce the synthesis of Drp1 protein and inhibit the mitochondrial fission of RA-FLSs, which was reversed by YAP agonists. Therefore, irisin has a protective effect on RA. CONCLUSION: Irisin inhibits the proliferation, migration, invasion and inflammatory response of RA-FLSs by inhibiting the YAP-Drp1 signaling pathway, which implies a potential therapeutic effect on RA.

Monocytes in rheumatoid arthritis: Circulating precursors of macrophages and osteoclasts and, their heterogeneity and plasticity role in RA pathogenesis.

Rheumatoid arthritis (RA) is a chronic systemic, autoimmune and inflammatory disease represented as synovitis, pannus formation, adjacent bone erosions, and joint destruction. The major cells involved in the perpetuation of RA pathogenesis are CD4+ T-cells (mainly Th1 cells and Th17 cells), fibroblasts like synoviocytes (FLS), macrophages and B cells. Other autoimmune cells such as dendritic cells, neutrophils, mast cells, and monocytes also contribute to RA pathogenesis. Monocytes are mainly bone marrow (BM) derived cells in the circulation. The chemokine receptors CCR2 and CX3CR1 expressed by monocytes interact with chemokine ligands CCL2 (MCP-1) and CX3CL1 (fractalkine) respectively produced by FLS and this interaction promotes their migration and recruitment into RA synovium. Activated monocytes on their surface exhibit upregulated antigenic expressions such as CD14, CD16, HLA-DR, toll-like receptors (TLRs), and adhesion molecules B1 and B2 integrins. RA monocytes interconnect with other cells in a positive loop manner in the propagation of the rheumatoid process. They skew towards mainly intermediate monocyte subsets (CD14++ CD16+) which produce proinflammatory cytokines such as TNF-α, IL-1ß, and IL-6. Moreover, the predominant intermediate monocytes in RA differentiate into M1-macrophages which play a major role in synovial inflammation. Demonstrations suggest monocytes with CD14+ and CD16- expression (classical monocytes?) differentiate to osteoclasts which are the cells responsible for bone erosion in RA synovial joints. Th17 cells induce the production of RANKL by FLS which promotes osteoclastogenesis. Cytokines mainly TNF-α, IL-1ß, and IL-6 amplify osteoclastogenesis. Hence, monocytes are the circulating precursors of macrophages and osteoclasts in RA. AIM OF THE REVIEW: To enlighten the identity of monocytes, the antigenic expression on monocyte surface and their cytokines role in RA. We also emphasize about the chemokine receptors expressed by monocytes subsets and chemotaxis of circulating monocytes into RA synovium. Additionally, we review monocytes as the circulating precursors of macrophages and osteoclasts in RA joints and their heterogeneity and plasticity role in RA.

Activation of the bile acid receptor GPBAR1 (TGR5) ameliorates interleukin-1ß (IL-1ß)- induced chondrocytes senescence.

Osteoarthritis is the most common chronic condition of the joint disease. Chondrocyte is the sole cell type in joint tissues. Senescence of chondrocytes is known to contribute to the causation of osteoarthritis. Local inflammatory cytokines- caused chondrocytes senescence is proposed to be one of the molecular mechanisms of osteoarthritis. In this study, we show that the bile acid receptor GPBAR1 (TGR5), a G protein couples bile acid receptor, plays important roles in protecting chondrocytes from interleukin 1ß (IL-1ß)- caused senescence. TGR5 is fairly expressed in cultured chondrocytes. Its expression is reduced in isolated chondrocytes from osteoarthritis patients, and IL-1ß treatment suppresses TGR5 expression. Activation of TGR5 by its synthetic agonist, INT-777, dramatically reduces senescence associated ß galactosidase activity by IL-1ß. Mechanistically, the action of INT-777 ameliorates IL-1ß- induced chondrocytes entry of G0/G1 arrest phase and exit of S and G2/M phases. INT-777 inhibits IL-1ß- induced expression of p21, PAI-1, and K382 acetylation of p53 as well as reduction of Sirt1. The knockdown of TRG5 abolished the protective role of INT-777 on these molecules. Collectively, our data indicates that activation of TGR5 is necessary for protection of IL-1ß- induced chondrocytes senescence.

A Single Microorganism Epitope Attenuates the Development of Murine Autoimmune Arthritis: Regulation of Dendritic Cells via the Mannose Receptor.

A single epitope of Leishmania analog of the receptors for activated C kinase (LACK) from Leishmania major, the polypeptide LACK156-173, is recognized by Vß4+/Vα8+ T cells, and activate these cells that drives the subsequent T helper (Th)2 response. This study was undertaken to investigate the therapeutic potential of the LACK156-173 epitope in murine autoimmune arthritis models. To explore the influence of the LACK156-173 epitope on murine collagen antibody-induced arthritis, as well as its immunological mechanism, we vaccinated or treated mice with a LACK156-173 epitope expression plasmid or polypeptide. The effect of LACK156-173 epitope was then evaluated by clinical scores, histopathology, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Using flow cytometry, we measured the subsets and maturity of CD11c+ dendritic cells (DCs), as well as T cell polarization, in co-culture experiments. We also measured cytokine gene expression and production. The murine macrophage-like cell line RAW264.7 was used to identify the receptor for the epitope. Vaccination or treatment of the mice with the LACK156-173 epitope expression plasmid or polypeptide ameliorated the severity of arthritis. qRT-PCR analysis revealed that the LACK156-173 epitope improved the balance of effector T cells in synovial tissue compared to that in untreated arthritis controls. Toll-like receptor (TLR) 4 expression was diminished by LACK156-173. The epitope also influenced T cell polarization by regulating the differentiation, maturation, and functions of CD11c+ DCs and upregulating Jagged1 ligand expression. Blocking the mannose receptor (MR) significantly attenuated LACK156-173 epitope-induced macrophage activation. Our data indicate that vaccination or treatment with a single microorganism epitope, LACK156-173, is a highly efficient therapy for murine autoimmune arthritis. The therapeutic effects are mediated by the regulation of the differentiation, maturation, and functions of DCs via MR, resulting in the upregulation of Jagged1 expression and Th2 cell polarization. Our results demonstrate the therapeutic potential of the LACK156-173 epitope in rheumatoid arthritis.

Inhibition of microRNA-34a ameliorates murine collagen-induced arthritis.

Rheumatoid arthritis (RA) is one of the most frequently occurring autoimmne diseases, with symptoms including synovium hyperplasia, immune disorder, cartilage damage and bone resorption. It has previously been demonstrated that microRNA-34a (miR-34a) may participate in cell apoptosis, immune activation and bone metabolism, therefore the present study investigated the effects of miR-34a on RA. Collagen-induced arthritic (CIA) mice were employed as a murine model of experimental arthritis, and it was demonstrated that the level of miR-34a in the spleens, lymph nodes and synovium was increased in the CIA mice compared with normal DBA/1j mice. Administration of miR-34a antagomir, the chemically modified inhibitor, ameliorated CIA and delayed the onset of symptoms. Arthritis scores decreased and joint swelling was alleviated with the miR-34a antagomir treatment and the expression of inflammatory cytokines was decreased. miR-34a antagomir delivery significantly decreased the percentage of T cells present including T helper (Th) 1, Th2, Th17 and regulatory T cells. Furthermore miR-34a antagomir-treated CIA mice demonstrated decreased inflammatory-induced bone loss. Overall, it was observed that inhibition of miR-34a ameliorated murine arthritis, downregulated T cell percentage and cytokine expression, and suppressed bone loss. The experimental results suggest that inhibition of miR-34a may offer a novel alternative for the treatment of RA.

Neuropsychiatric involvement in lupus is associated with the Nogo-a/NgR1 pathway.

Neuroinflammation- and neurodegeneration-induced nerve injury may represent important components of neuropsychiatric lupus (NPSLE). Myelin-associated neurite outgrowth inhibitor (Nogo)-a and its receptor, NgR1, limit recovery of the adult central nervous system after injury. We detected a soluble Nogo-a product in the cerebral spinal fluid of patients with NPSLE. In a mouse model of lupus, aging was associated with an increase in Nogo-a positive neurons, diminished myelin sheaths, enhanced pro-inflammatory cytokines, and impaired cognition and memory. Treatment with the Nogo-66 antagonist promoted myelin repair, improved cognition and memory, and downregulated pro-inflammatory factors. Our data imply the Nogo-a/NgR1 pathway is involved in NPSLE.

Intra-Articular Injection of Human Synovial Membrane-Derived Mesenchymal Stem Cells in Murine Collagen-Induced Arthritis: Assessment of Immunomodulatory Capacity In Vivo.

The aim of this study was to evaluate the efficacy of human synovial membrane-derived MSCs (SM-MSCs) in murine collagen-induced arthritis (CIA). Male mice (age 7-9 weeks) were injected intra-articularly with SM-MSCs obtained from patients with osteoarthritis, on days 28, 32, and 38 after bovine type II collagen immunization. The efficacy of SM-MSCs in CIA was evaluated clinically and histologically. Cytokine profile analyses were performed by real-time polymerase chain reaction and multiplex analyses. Splenic helper T (Th) cell and regulatory B cell subsets were analyzed by flow cytometry. Intra-articular SM-MSC injection ameliorated the clinical and histological severity of arthritis. Decrease in tumor necrosis factor-α, interferon-γ, and interleukin- (IL-) 17A and increase in IL-10 production were observed after SM-MSC treatment. Flow cytometry showed that Th1 and Th17 cells decreased, whereas Th2, regulatory T (Treg), and PD-1+CXCR5+FoxP3+ follicular Treg cells increased in the spleens of SM-MSC-treated mice. Regulatory B cell analysis showed that CD21hiCD23hi transitional 2 cells, CD23lowCD21hi marginal zone cells, and CD19+CD5+CD1d+IL-10+ regulatory B cells increased following SM-MSC treatment. Our results demonstrated that SM-MSCs injected in inflamed joints in CIA had a therapeutic effect and could prevent arthritis development and suppress immune responses via immunoregulatory cell expansion.