Mast Cells In Rheumatoid Arthritis Research Articles

Mast Cell Involvement in the Pathogenesis of Selected Musculoskeletal Diseases.

In recent years, there has been a noteworthy revival of interest in the function of mast cells (MCs) in the human body. It is now acknowledged that MCs impact a wide array of processes beyond just allergies, leading to a shift in research direction. Unfortunately, some earlier conclusions were drawn from animal models with flawed designs, particularly centered around the receptor tyrosine kinase (Kit) pathway. Consequently, several subsequent findings may have been unreliable. Thus, what is now required is a re-examination of these earlier findings. Nevertheless, the remaining data are fascinating and hold promise for a better comprehension of numerous diseases and the development of more effective therapies. As the field continues to progress, many intriguing issues warrant further investigation and analysis. For instance, exploring the bidirectional action of MCs in rheumatoid arthritis, understanding the extent of MCs' impact on symptoms associated with Ehlers-Danlos syndrome, and unraveling the exact role of the myofibroblast-mast cell-neuropeptides axis in the joint capsule during post-traumatic contractures are all captivating areas for exploration. Hence, in this review, we summarize current knowledge regarding the influence of MCs on the pathogenesis of selected musculoskeletal diseases, including rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, gout, muscle and joint injuries, tendinopathy, heterotopic ossification, and Ehlers-Danlos syndrome. We believe that this review will provide in-depth information that can guide and inspire further research in this area.

Regulation of osteoclastogenesis by mast cell in rheumatoid arthritis

BackgroundIn the pathogenesis of rheumatoid arthritis (RA), the role of mast cells has not been revealed clearly. We aimed to define the inflammatory and tissue-destructive roles of mast cells in rheumatoid arthritis (RA).MethodsSerum and synovial fluid (SF) concentration levels of tryptase, chymase, and histamine were quantified using ELISA. After activating mast cells using IL-33, the production of TNF-α, IL-1β, IL-6, IL-17, RANKL, and MMPs was determined using real-time PCR and ELISA. Osteoclastogenesis was assessed in CD14+ monocytes from peripheral blood and SF, which were cultured with IL-33-activated mast cells, by counting TRAP-positive multinucleated cells.ResultsThe concentration levels of serum tryptase, chymase, and histamine and SF histamine were higher in patients with RA than in controls. FcεR1 and c-kit-positive mast cells were higher in RA synovium than in osteoarthritic (OA) synovium. Stimulation of mast cells by IL-33 increased the number of trypatse+chymase− and tryptase+chymase+ mast cells. IL-33 stimulation also increased the gene expression levels of TNF-α, IL-1β, IL-6, IL-17, RANKL, and MMP-9 in mast cells. Furthermore, IL-33 stimulated human CD14+ monocytes to differentiate into TRAP+ multinucleated osteoclasts. When CD14+ monocytes were co-cultured with mast cells, osteoclast differentiation was increased. Additionally, IL-33-activated mast cells stimulated osteoclast differentiation. The inhibition of intercellular contact between mast cells and monocytes using inserts reduced osteoclast differentiation.ConclusionsIL-33 increased inflammatory and tissue-destructive cytokines by activation of mast cells. Mast cells stimulated osteoclast differentiation in monocytes. Mast cells could stimulate osteoclastogenesis indirectly through production of tissue-destructive cytokines and directly through stimulation of osteoclast precursors.

Higher PGD2 production by synovial mast cells from rheumatoid arthritis patients compared with osteoarthritis patients via miR-199a-3p/prostaglandin synthetase 2 axis

We previously reported that synovial mast cells (MCs) from patients with rheumatoid arthritis (RA) produced TNF-α in response to immune complexes via FcγRI and FcγRIIA. However, the specific functions of synovial MCs in RA remain unclear. This study aimed to elucidate those functions. Synovial tissues and fluid were obtained from RA and osteoarthritis (OA) patients undergoing joint replacement surgery. Synovium-derived, cultured MCs were generated by culturing dispersed synovial cells with stem cell factor. We performed microarray-based screening of mRNA and microRNA (miRNA), followed by quantitative RT-PCR-based verification. Synovial MCs from RA patients showed significantly higher prostaglandin systhetase (PTGS)1 and PTGS2 expression compared with OA patients’ MCs, and they produced significantly more prostaglandin D2 (PGD2) following aggregation of FcγRI. PGD2 induced IL-8 production by human group 2 innate lymphoid cells, suggesting that PGD2-producing MCs induce neutrophil recruitment into the synovium of RA patients. PTGS2 mRNA expression in RA patients’ MCs correlated inversely with miRNA-199a-3p expression, which down-regulated PTGS2. RA patients’ synovial fluid contained significantly more PGD2 compared with OA patients’ fluid. Synovial MCs might regulate inflammation in RA through hyper-production of PGD2 following FcRγ aggregation. Our findings indicate functional heterogeneity of human MCs among diseases.

Roles of mast cells in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory arthritis, and the complex interaction and activation of innate and adaptive immune cells are involved in RA pathogenesis. Mast cells (MCs) are one of the tissue-resident innate immune cells, and they contribute to RA pathogenesis. In the present review, the evidence of the pathologic role of MC in RA is discussed based on human and animal data. In addition, the potential role of MC in RA pathogenesis and the research area that should be focused on in the future are suggested.

Mast Cells in Early Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation of the synovial membrane, with thickening of the synovial layer, cellular hyperplasia, and infiltration of immune cells. Mast cells (MCs) are cells of the innate immunity present in healthy synovia and part of the cellular hyperplasia characterizing RA synovitis. Although their presence in synovia has been well described, the exact functions and the correlation of MCs with disease development and progression have been debated, particularly because of contradictory data obtained in animal models and from patients with longstanding disease. Here, we present a revision of the literature on MCs in RA, including the most recent observations obtained from patients with early RA, indicating MCs as relevant markers of disease severity in early RA.

The dual regulation of substance P-mediated inflammation via human synovial mast cells in rheumatoid arthritis

BackgroundNeural pathways are thought to be directly involved in the pathogenesis of rheumatoid arthritis (RA). Although synovial mast cells (MCs) are activated by substance P (SP), the role of MCs in neural pathways in RA remains unknown. The aims of this study were to investigate 1) whether tachykinins are produced by synovial MCs and whether production differs in RA and osteoarthritis (OA) patients, and 2) what is the responsible receptor for SP in synovial MCs. MethodsSynovial tissues were obtained from patients with RA or OA undergoing joint replacement surgery. Cultured synovium-derived MCs were generated by culturing dispersed synovial cells with stem cell factor. SP expression was investigated using immunofluorescence and enzyme immunoassays. Mas-related gene X2 (MrgX2) expression was reduced in human MCs using a lentiviral shRNA silencing technique. ResultsSP expression was localized around the cell membrane in 41% (median) of the MCs in synovium from RA but in only 7% of that from OA, suggesting the activation of MCs. Synovial MCs expressed tachykinin (TAC) 1 mRNA, the expression of which was upregulated by the aggregation of FcɛRI or the addition of aggregated IgG. However, the released SP appeared to be rapidly degraded by MC chymase. Synovial MCs were activated with SP through MrgX2 to release histamine without producing proinflammatory cytokines. ConclusionsActivated synovial MCs may rapidly degrade SP, which may downregulate the SP-mediated activation of synoviocytes in RA. On the other hand, SP activates MCs to induce inflammatory mediators, suggesting the dual regulation of SP-mediated inflammation by MCs in RA.

Interleukin-17A expression in human synovial mast cells in rheumatoid arthritis and osteoarthritis

BackgroundInterleukin (IL)-17A plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The expression of IL-17A in synovial mast cells (MCs) in RA and osteoarthritis (OA) has been reported, but the frequencies of IL-17A expression in synovial MCs have varied. The aim of this study was to investigate whether IL-17A expression is upregulated in human synovial MCs in RA and to elucidate the mechanism of IL-17A expression in synovial MCs. MethodsSynovial tissues were obtained from patients with RA or OA undergoing joint replacement surgery, and synovial MCs were enzymatically dispersed. Synovium-derived cultured MCs were generated by culturing synovial cells with stem cell factor. IL-17A expression was investigated using immunofluorescence in synovial tissues. IL-17A mRNA expression and its production from MCs were examined using RT-PCR and ELISA, respectively. ResultsThe number of IL-17A-positive (+) synovial MCs and the percentage of IL-17A+ MCs among all the IL-17A+ cells from RA patients were not significantly increased compared with those from OA subjects. The synovium-derived cultured MCs spontaneously released small amounts of IL-17A. Neither IgE- nor IgG-dependent stimulation increased IL-17A production from the MCs. IL-33, tumor necrosis factor-α, C5a, lipopolysaccharide or IL-23 plus IL-1β did not affect IL-17A production in MCs. ConclusionsThe synovial MCs are not a main source of IL-17A in RA.

Mast cell–derived tryptase inhibits apoptosis of human rheumatoid synovial fibroblasts via rho‐mediated signaling

An abundance of mast cells are found in the synovium of patients with rheumatoid arthritis (RA). However, the role of mast cells in the pathogenesis of RA remains unclear. This study was undertaken to elucidate a role for mast cells in RA by investigating the antiapoptotic effects of tryptase, a major product of mast cells, on RA synovial fibroblasts (RASFs). RA synovial tissue was obtained from RA patients during joint replacement surgery, and histologic changes in the tissue were examined. The expression of cell surface molecules and apoptotic markers on RASFs were detected by flow cytometry. Rho activation was determined using a pull-down assay. Mast cells, bearing both c-Kit and tryptase, accumulated in the sublining area of proliferating synovial tissue from RA patients. Protease-activated receptor 2 (PAR-2), a receptor for tryptase, was expressed on RASFs in the lining area, close to tryptase-positive mast cells in the RA synovium. Fas-mediated apoptosis of RASFs was significantly inhibited, in a dose-dependent manner, by the addition of tryptase, and this effect correlated with increased activation of Rho kinase. Furthermore, Y27632, a Rho kinase inhibitor, reduced the antiapoptotic effect of tryptase on RASFs, suggesting that Rho was responsible for the antiapoptotic effects of tryptase. These results demonstrate that tryptase has a strong antiapoptotic effect on RASFs through the activation of Rho. Thus, we propose that the release of tryptase by mast cells leads to the binding of tryptase to PAR-2 on RASFs and inhibits the apoptosis of RASFs via the activation of Rho. Such mechanisms could play a pivotal role in the marked proliferation of RASFs and hyperplasia of synovial tissue seen in RA synovium.

Leukotrienes, mast cells, and T cells

Leukotrienes, mast cells, and T cells

Mast cells as a target in the treatment of rheumatoid arthritis

Mast cells represent a unique cell population, which is involved in a number of immune responses in our body. Mast cells (MCs) release an array of potent pro-inflammatory mediators and cytokines upon activation that are either pre-stored in the granules or synthesised de novo. These mediators can make a substantial contribution to the initiation and perpetuation of the inflammatory processes. This review provides an insight for the potential role of MCs in rheumatoid arthritis (RA). The data on mast cell distribution in the rheumatoid joint along with the information obtained from in vitro experiments and observations in animal models suggest that these cells may be involved in RA. The encouraging results of MC inactivating therapy in animal models of arthritis indicate that MC stabilizers may prove beneficial as a supplementary therapy in RA.

Quantitation of human synovial mast cells in rheumatoid arthritis and other rheumatic diseases.

We examined sections of synovial membranes from 14 patients with rheumatoid arthritis (RA), 7 with other rheumatic diseases, and 10 with no apparent joint disease. Patients with RA and other rheumatic diseases had significantly more synovial mast cells/vessel than patients with no joint disease (0.49 and 0.20, respectively, versus 0.03). They also had significantly more total mast cells/10 fields than patients with no joint disease (9.9 and 5.0, respectively, versus 0.4). Within the rheumatoid group, patients with active disease had more total mast cells/10 fields than patients clinically considered to have end-stage disease (P less than 0.05). Synovial basophils were not identified in any patient. Synovial vascularity was similar for all groups (2.3 vessels/field). The role of the synovial mast cell in RA and other rheumatic diseases remains to be determined.