CCR5 is involved in resolution of inflammation in proteoglycan-induced arthritis.

Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by joint infiltration by several populations of leukocytes including T cells, B cells, macrophages and neutrophils (1). These infiltrating cells, in collaboration with resident cells, mediate cartilage destruction and bone erosion through a combination of cytokines, chemokines and matrix metalloproteases, (2)(3). In synovial fluid of RA patients, all four groups of chemokine families, CXC, CC, C and CX3C, and their receptors have been identified (3). The inhibition of infiltrating cells into the joint therefore represents an important step for therapeutic intervention. Chemokine (C-C motif) receptor 5 (CCR5), is a G-protein coupled chemokine receptor composed of seven transmembrane helices that is expressed by activated T cells, monocytes, dendritic cells, tissue macrophages, and neutrophils (4, 5). CCR5 is the natural receptor for the ligands CCL3 (MIP-1α), CCL4 (MIP-1β), and CCL5 (RANTES) all of which contribute to chemotactic activity in the synovial fluid of RA patients (6–8). The accumulation of CCR5+ T cells in the synovium of patients with RA suggests an important role in disease pathology (8). However, the chemotactic responses to RA synovial fluid were not dependent solely on a functional CCR5 receptor (9). The CCR5+ T cells express other chemokine receptors such as CCR1 which are also capable of responding to CCL3 and CCL5 (9). An allelic form of the CCR5 gene contains a 32-bp deletion (Δ32CCR5) which results in a nonfunctional CCR5 receptor. Several studies have addressed whether a loss of function mutation could have a protective effect against RA. Two of these studies demonstrated a statistical significant negative correlation between Δ32CCR5 and RA (10, 11) whereas three other studies were not significant (12–14). More recently, a meta-analysis of these 5 published studies demonstrated a significant negative association of Δ32CCR5 with RA (15) suggesting that - at least in the population of European ancestry - it may be protective. Treatment with a modified form of RANTES known as Met-RANTES, mildly inhibits arthritis in collagen-induced arthritis (CIA) and adjuvant induced arthritis (AIA) (15–17); however, these studies did not exclude the possibility that Met-RANTES interaction with CCR1 mediates inhibition. Use of a non-peptide antagonist of CCR5 in CIA revealed intact cellular immune responses but impaired T cell migration (16). Contrary to these findings, CIA in CCR5-deficient mice is similar to wild type mice (17). A novel role for CCR5 in the clearance of inflammation was recently elucidated. Early clues suggesting an anti-inflammatory role of CCR5 showed that the CCR5 antagonist Met-RANTES affected the uptake of apoptotic cells in a model of glomerulonephritis (18). Similarly, a deficiency in CCR5 or blocking CCR5 enhanced pathogenic inflammatory responses in hepatic liver disease, pancreatitis and glomerulonephritis (18–20). An important mechanistic explanation for these phenomena revealed that CCR5 may act as a novel decoy receptor on late apoptotic neutrophils and T cells. In this way, CCR5 can function to remove excess CCL3, CCL4, and CCL5 from tissue in the presence of pro-resolution lipid mediators (5). In this study we use an established model of RA, proteoglycan-induced arthritis (PGIA), to examine the function of CCR5 in disease. We found that CCR5 function is important in the clearance of CCL5 thereby promoting the resolution of inflammation.