Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice

Waka Yokoyama, Hitoshi Kohsaka, Kayoko Kaneko, Matthew Walters, Aiko Takayasu, Shin Fukuda, Chie Miyabe, Yoshishige Miyabe, Paul E. Love, Nobuhiro Nakamoto, Takanori Kanai, Kaori Watanabe-Imai, Trevor T. Charvat, Mark E.T. Penfold, Juan Jaen, Thomas J. Schall, Masayoshi Harigai, Nobuyuki Miyasaka, Toshihiro Nanki

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19 Citations (Scopus)

Abstract

Introduction: Biological drugs are effective in patients with rheumatoid arthritis (RA), but increase severe infections. The CC chemokine receptor (CCR) 9 antagonist was effective for Crohn's disease without critical adverse effects including infections in clinical trials. The present study was carried out to explore the pathogenic roles of chemokine (C-C motif) ligand (CCL) 25 and its receptor, CCR9, in autoimmune arthritis and to study if the CCR9 antagonist could be a new treatment for RA. Methods: CCL25 and CCR9 expression was examined with immunohistochemistry and Western blotting. Concentration of interleukin (IL)-6, matrix metalloproteinase (MMP)-3 and tumor necrosis factor (TNF)-α was measured with enzyme-linked immunosorbent assays. Effects of abrogating CCR9 on collagen-induced arthritis (CIA) was evaluated using CCR9-deficient mice or the CCR9 antagonist, CCX8037. Fluorescence labeled-CD11b+ splenocytes from CIA mice were transferred to recipient CIA mice and those infiltrating into the synovial tissues of the recipient mice were counted. Results: CCL25 and CCR9 proteins were found in the RA synovial tissues. CCR9 was expressed on macrophages, fibroblast-like synoviocytes (FLS) and dendritic cells in the synovial tissues. Stimulation with CCL25 increased IL-6 and MMP-3 production from RA FLS, and IL-6 and TNF-α production from peripheral blood monocytes. CIA was suppressed in CCR9-deficient mice. CCX8037 also inhibited CIA and the migration of transferred CD11b+ splenocytes into the synovial tissues. Conclusions: The interaction between CCL25 and CCR9 may play important roles in cell infiltration into the RA synovial tissues and inflammatory mediator production. Blocking CCL25 or CCR9 may represent a novel safe therapy for RA.

Original languageEnglish
Article number445
JournalArthritis Research and Therapy
Volume16
Issue number1
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

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    Yokoyama, W., Kohsaka, H., Kaneko, K., Walters, M., Takayasu, A., Fukuda, S., Miyabe, C., Miyabe, Y., Love, P. E., Nakamoto, N., Kanai, T., Watanabe-Imai, K., Charvat, T. T., Penfold, M. E. T., Jaen, J., Schall, T. J., Harigai, M., Miyasaka, N., & Nanki, T. (2014). Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice. Arthritis Research and Therapy, 16(1), [445]. https://doi.org/10.1186/s13075-014-0445-9