Yuki Okamura1, Shintaro Mishima1, Jun-Ichi Kashiwakura2, Tomomi Sasaki-Sakamoto2, Shota Toyoshima2, Kazumichi Kuroda3, Shu Saito4, Yasuaki Tokuhashi4, Yoshimichi Okayama5. 1. Allergy and Immunology Project Team, Nihon University School of Medicine, Tokyo, Japan; Department of Orthopedic Surgery, Nihon University School of Medicine, Tokyo, Japan. 2. Allergy and Immunology Project Team, Nihon University School of Medicine, Tokyo, Japan; Division of Medical Education Planning and Development, Nihon University School of Medicine, Tokyo, Japan. 3. Department of Microbiology, Nihon University School of Medicine, Tokyo, Japan. 4. Department of Orthopedic Surgery, Nihon University School of Medicine, Tokyo, Japan. 5. Allergy and Immunology Project Team, Nihon University School of Medicine, Tokyo, Japan; Division of Medical Education Planning and Development, Nihon University School of Medicine, Tokyo, Japan. Electronic address: okayama.yoshimichi@nihon-u.ac.jp.
Abstract
BACKGROUND: Neural 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. METHODS: Synovial 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. RESULTS: SP 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. CONCLUSIONS: Activated 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.
BACKGROUND: Neural 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. METHODS: Synovial 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. RESULTS:SP 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. CONCLUSIONS: Activated 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.
Authors: Alexandra Taracanova; Irene Tsilioni; Pio Conti; Errol R Norwitz; Susan E Leeman; Theoharis C Theoharides Journal: Proc Natl Acad Sci U S A Date: 2018-09-19 Impact factor: 11.205