Published in:
Open Access
01-10-2014 | Research article
Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice
Authors:
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 ET Penfold, Juan Jaen, Thomas J Schall, Masayoshi Harigai, Nobuyuki Miyasaka, Toshihiro Nanki
Published in:
Arthritis Research & Therapy
|
Issue 5/2014
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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.