Abstract
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.
Highlights
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by immune cell-mediated destruction of the architecture of joints
Some PGs, such as the nonenzymatic P GD2 metabolite 15-deoxy-PGJ2, have anti-inflammatory effects depending on the disease c ontext11. PGD2 may exert pro-inflammatory or anti-inflammatory effects in different biologic systems15. PGD2 is a ligand for two receptors, D prostanoid (DP) and chemoattractant receptor-homologous molecule expressed on T helper 2 (Th2) cells (CRTH2)15. PGH2 is converted to P GD2 by two enzymes, hematopoietic PGD synthase (HPGDS) and lipocalin-type PGDS (LPGDS)
We show that human synovial mast cells (MCs) from rheumatoid arthritis (RA) patients produced greater amounts of P GD2 via the PTGS2-miR-199a-3p axis compared with MCs from OA patients
Summary
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by immune cell-mediated destruction of the architecture of joints Proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-17, are thought to play pivotal roles in that joint architecture destruction in RA patients. We previously reported that aggregated IgG induces TNF-α production by human synovium-derived, cultured MCs via FcγRI and FcγRII7 and that IL-33 synergistically enhances immune complex-induced TNF-α and IL-8 production in those same cells[8] These results suggest that activation of MCs may exaggerate inflammation in RA. A clinical study found high concentrations of PGD2 in the SF of patients with RA, and PGD2 and HPGDS expressions were inversely associated with serum C-reactive protein (P < 0.01)[22] These findings suggest that P GD2 is an active agent in the resolution of inflammation in experimentally induced murine arthritis and in human RA. Elevated P GD2 production in RA patients’ MCs might play an important role in the pathogenesis of RA
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