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

Abstract

IntroductionBiological 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.MethodsCCL25 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.ResultsCCL25 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.ConclusionsThe 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.

Chemokine interaction with synergy-inducing molecules: fine tuning modulation of cell trafficking

“…This renders the chemokine system a good target for therapy and has promoted the search, by pharmaceutical companies, for small-molecule chemokine antagonists [8–10]. Although we understand well the effects of different chemokines one by one, much less was known about the potential consequences of the concomitant expression of multiple chemokines or of their interaction with inflammatory molecules on leukocyte migration and function [11, 12].…”

Abrogation of CC chemokine receptor 9 ameliorates ventricular remodeling in mice after myocardial infarction

“…The use of neutralizing antibodies in animal disease models has proven to be effective141619202122. CCR9−/− mice did not develop hepatitis following conA injection14, and the abrogation of CCR9 ameliorates collagen-induced arthritis in mice23. However, other studies have shown that CCR9−/− mice are more susceptible to DSS-induced colitis2224.…”

Enhanced CCR9 expression levels in psoriatic skin are associated with poor clinical outcome to infliximab treatment

“…There are no reports about the role of CCR9 in dermatological diseases including psoriasis. However, CCR9 receives a lot of attention in regard to the pathogenesis of autoimmune diseases including Crohn's disease (CD) and rheumatoid arthritis (RA) . Furthermore, clinical trials of CCR9 inhibitors have been initiated in patients with CD …”

“…It is involved in lymphocyte migration . As stated previously, CCR9 plays an important role in inflammatory diseases including CD and RA . Although anti TNF‐α antibodies have proven to be highly effective, as in the case of psoriasis, not all patients respond to treatment with TNF‐α inhibitors.…”

“…Although anti TNF‐α antibodies have proven to be highly effective, as in the case of psoriasis, not all patients respond to treatment with TNF‐α inhibitors. Recent reports have indicated that a CCR9 inhibitor improves the disease progress in experimental mouse models of CD and RA . Moreover, anti‐CCR9 therapies have recently been developed in new clinical trials for CD.…”