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

Research output: Contribution to journalArticle

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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.

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

Fingerprint

Experimental Arthritis
Rheumatoid Arthritis
Interleukin-6
Matrix Metalloproteinase 3
Tumor Necrosis Factor-alpha
Fibroblasts
CC Chemokines
Infection
Crohn Disease
Dendritic Cells
Arthritis
CC chemokine receptor 9
Monocytes
Fluorescence
Western Blotting
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Macrophages
Clinical Trials
Ligands

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Yokoyama, W., Kohsaka, H., Kaneko, K., Walters, M., Takayasu, A., Fukuda, S., ... 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

Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice. / Yokoyama, Waka; Kohsaka, Hitoshi; Kaneko, Kayoko; Walters, Matthew; Takayasu, Aiko; Fukuda, Shin; Miyabe, Chie; Miyabe, Yoshishige; Love, Paul E.; Nakamoto, Nobuhiro; Kanai, Takanori; Watanabe-Imai, Kaori; Charvat, Trevor T.; Penfold, Mark E.T.; Jaen, Juan; Schall, Thomas J.; Harigai, Masayoshi; Miyasaka, Nobuyuki; Nanki, Toshihiro.

In: Arthritis Research and Therapy, Vol. 16, No. 1, 445, 2014.

Research output: Contribution to journalArticle

Yokoyama, W, Kohsaka, H, Kaneko, K, Walters, M, Takayasu, A, Fukuda, S, Miyabe, C, Miyabe, Y, Love, PE, Nakamoto, N, Kanai, T, Watanabe-Imai, K, Charvat, TT, Penfold, MET, Jaen, J, Schall, TJ, Harigai, M, Miyasaka, N & Nanki, T 2014, 'Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice', Arthritis Research and Therapy, vol. 16, no. 1, 445. https://doi.org/10.1186/s13075-014-0445-9
Yokoyama, Waka ; Kohsaka, Hitoshi ; Kaneko, Kayoko ; Walters, Matthew ; Takayasu, Aiko ; Fukuda, Shin ; Miyabe, Chie ; Miyabe, Yoshishige ; Love, Paul E. ; Nakamoto, Nobuhiro ; Kanai, Takanori ; Watanabe-Imai, Kaori ; Charvat, Trevor T. ; Penfold, Mark E.T. ; Jaen, Juan ; Schall, Thomas J. ; Harigai, Masayoshi ; Miyasaka, Nobuyuki ; Nanki, Toshihiro. / Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice. In: Arthritis Research and Therapy. 2014 ; Vol. 16, No. 1.
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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.",
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AU - Yokoyama, Waka

AU - Kohsaka, Hitoshi

AU - Kaneko, Kayoko

AU - Walters, Matthew

AU - Takayasu, Aiko

AU - Fukuda, Shin

AU - Miyabe, Chie

AU - Miyabe, Yoshishige

AU - Love, Paul E.

AU - Nakamoto, Nobuhiro

AU - Kanai, Takanori

AU - Watanabe-Imai, Kaori

AU - Charvat, Trevor T.

AU - Penfold, Mark E.T.

AU - Jaen, Juan

AU - Schall, Thomas J.

AU - Harigai, Masayoshi

AU - Miyasaka, Nobuyuki

AU - Nanki, Toshihiro

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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