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

Abstract

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 factora (TNFa) production. In the LPS model, CCR1 knockout, adrenalectomised, or IL-10-depleted mice were also used. Production of TNFa 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 TNFa levels in LPS-treated mice. Surprisingly, CCR1 knockout mice produced more TNFa 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 TNFa production by J-113863. The compound did not inhibit mouse TNFa in vitro, but did induce a trend towards increased TNFa 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.

Chemokine (C-C Motif) Receptor 1 Is Required for Efficient Recruitment of Neutrophils during Respiratory Infection with Modified Vaccinia Virus Ankara

“…infected with MVA and treated with the well-characterized CCR1 antagonist J-113863 (41,42) or an equivalent amount of vehicle. BAL was performed 16 h after infection, and cells in the BAL fluid were analyzed with flow cytometry.…”

“…On the other hand, treatment of mice with a CCR1 antagonist nearly completely prevented neutrophil recruitment at 16 h postinfection. However, J-113863, the CCR1 antagonist used, has been shown to interfere with tumor necrosis factor alpha (TNF-␣) (41), which is also involved in neutrophil recruitment (53); therefore, the offtarget effects of J-113863 may potentiate the effects of CCR1 inhibition. Based on our results, it is tempting to speculate that CCR1 and CXCR2 ligands may interact in a synergistic manner to enable optimal recruitment of neutrophils.…”

Role of CCL7 in Type I Hypersensitivity Reactions in Murine Experimental Allergic Conjunctivitis

“…Mice in which CCL3 is deficient or neutralized fail to display typical allergic symptoms after ocular exposure to allergen. In other allergic diseases, mice deficient for CCR1 display reduced inflammatory responses (18)(19)(20), and treatment with a CCR1 antagonist reduced inflammation in a mouse model of allergic asthma (21). CCR1 is expressed by conjunctival mast cells, and subconjunctival injection of CCL3 increases conjunctival mast cell number and degranulation in vivo (7).…”

Involvement of CC Chemokine Receptor 1 and CCL3 in Acute and Chronic Inflammatory Pain in Mice

“…We have no mechanistic explanation for the exclusive effect of J113863 on allodynia induced by CFA, but the duration of the inflammatory process rather than the inflammatory agent used seems to be critical for differences in response since the early acute allodynia detected 6 hr after CFA administration was also CCR1-insensitive, as occurred 6 hr after carrageenan. The poor ability of a quaternary ammonium compound such as J113863 [28] to cross the blood-brain barrier makes unlikely the involvement of spinal mechanisms in its anti-allodynic effect in chronic inflammation. The different response to J113863 in carrageenan-or CFA-treated mice seems unrelated to changes in the expression of CCL3 or CCL5 in inflamed tissues because it was similar after carrageenan or CFA treatment.…”

“…This possibility seemed feasible because the acute treatment with J113863 prior to the inflammatory stimulus can prevent cell infiltration or inhibit the production of particular chemokines and TNF-a [23] and consistent antiinflammatory responses can be achieved after its chronic administration [28]. We initially checked that a single administration of dexamethasone (10 mg/kg) effectively reduced paw swelling in inflamed mice.…”