Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo

Background and purpose: The chemokine receptor CCR1 is a potential target for the treatment of rheumatoid arthritis. To explore the impact of CCR1 blockade in experimental arthritis and the underlying mechanisms, we used J-113863, a non-peptide antagonist of the mouse receptor. Experimental approach: Compound J-113863 was tested in collagen-induced arthritis (CIA) and three models of acute inflammation; Staphylococcus enterotoxin B (SEB)-induced interleukin-2 (IL-2), delayed-type hypersensitivity (DTH) response, and lipopolysaccharide (LPS)-induced tumour necrosis factor alpha (TNF alpha) production. In the LPS model, CCR1 knockout, adrenalectomised, or IL-10-depleted mice were also used. Production of TNF alpha by mouse macrophages and human synovial membrane samples in vitro were also studied. Key results: Treatment of arthritic mice with J-113863 improved paw inflammation and joint damage, and dramatically decreased cell infiltration into joints. The compound did not inhibit IL-2 or DTH, but reduced plasma TNF alpha levels in LPS-treated mice. Surprisingly, CCR1 knockout mice produced more TNF alpha than controls in response to LPS, and J-113863 decreased TNFa also in CCR1 null mice, indicating that its effect was unrelated to CCR1. Adrenalectomy or neutralisation of IL-10 did not prevent inhibition of TNF alpha production by J-113863. The compound did not inhibit mouse TNF alpha in vitro, but did induce a trend towards increased TNF alpha release in cells from synovial membranes of rheumatoid arthritis patients. Conclusions and implications: CCR1 blockade improves the development of CIA, probably via inhibition of inflammatory cell recruitment. However, results from both CCR1-deficient mice and human synovial membranes suggest that, in some experimental settings, blocking CCR1 could enhance TNF production.