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Chemokines and Their Receptors in Rheumatoid Arthritis

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Chemokines and Their Receptors in Rheumatoid Arthritis ARTHRITIS & RHEUMATISM Vol. 52, No. 3, March 2005, pp 710–721 DOI 10.1002/art.20932 © 2005, American College of Rheumatology REVIEW Chemokines and Their Receptors in Rheumatoid Arthritis Future Targets? Alisa E. Koch Introduction tem was introduced in 2000, in which chemokines are considered as chemokine ligands, and each chemokine Rheumatoid arthritis (RA) is a chronic inflam- has been assigned a designation of CXCL, CCL, XCL, matory disease leading to joint destruction (1). In RA, or CX3CL1 (Figure 1) (10–12). In this report, both the migration of leukocytes into the synovial tissue (ST) former and new nomenclature are noted. occurs. These leukocytes and other cells in the ST, particularly RA ST fibroblasts, produce mediators of CXC chemokines have 2 conserved cysteines inflammation, including chemokines (1). Chemokines, separated by 1 unconserved amino acid (9,13) (Figure currently numbering more than 50, are chemotactic 1). CXC chemokines classically were thought to be cytokines that are important in recruitment of leuko- involved in the chemotaxis of neutrophils. Many chemo- cytes and angiogenesis. They exert chemotactic activity kines may have arisen from reduplication of ancestral toward a variety of cell types (2–7). Some chemokines, genes (13). Hence, CXC chemokines that act on neutro- particularly CXC chemokines containing the ELR motif, phils are clustered on chromosome 4q12–13 (13). How- are angiogenic. The last few years have seen a rapid ever, some genes of more newly discovered CXC che- development of studies aimed at targeting proinflamma- mokines that recruit lymphocytes tend to be located tory chemokines or their receptors in RA and animal away from the major clusters (13). This diversification models of RA (8,9). This review summarizes many of the may reflect functional specialization. Another function important developments in this field. Based on the of CXC chemokines is to modulate angiogenesis number of recently published studies, it is likely that the (7,14,15). In general, chemokines containing the ELR next few years will bring several new preclinical and motif, such as interleukin-8 (IL-8)/CXCL8, epithelial clinical trials targeting chemokines. neutrophil–activating peptide 78 (ENA-78)/CXCL5, growth-related oncogene ␣ (GRO␣)/CXCL1, and con- nective tissue activating peptide III (CTAP-III)/CXCL7, Chemokines promote angiogenesis. Conversely, ELR-lacking chemo- Chemokines have been classified into 4 super- kines, including platelet factor 4 (PF-4)/CXCL4, gene families based on the location of cysteine residues interferon-␥–inducible 10-kd protein (IP-10)/CXCL10, and monokine induced by IFN␥ (Mig)/CXCL9, inhibit (Figure 1). The 4 groups are CXC, CC, C, and CX3C chemokines (10–12). A relatively new classification sys- neovascularization (7,15,16). Contrary to this paradigm, the ELR-lacking stromal cell–derived factor 1 (SDF-1)/ Supported by NIH grants AR-48267, AI-40987, HL-58695, CXCL12 is angiogenic (5,16). the Frederick G. L. Huetwell and William D. Robinson MD Profes- CC chemokines have adjacent cysteine residues sorship in Rheumatology, and funds from the Veterans Administration Research Service. (Figure 1) (8,13). These chemokines classically were Alisa E. Koch, MD: University of Michigan Medical School, thought to induce monocyte chemotaxis, although many Ann Arbor, and Veteran’s Administration, Ann Arbor Healthcare members of this group may also recruit other cell types System, Ann Arbor, Michigan. Address correspondence and reprint requests to Alisa E. such as lymphocytes. As with CXC chemokines, many of Koch, MD, University of Michigan Medical School, 1150 West Med- the genes encoding CC chemokines are clustered, in this ical Center Drive, 5520 MSRB I, Ann Arbor, MI 48109-0680. E-mail: case on human chromosome 17q11.2 (4,8,13). Genes of [email protected]. Submitted for publication October 5, 2004; accepted in re- CC chemokines recruiting lymphocytes are not found in vised form December 13, 2004. this cluster in general. 710 TARGETING CHEMOKINES IN RA 711 Figure 1. Chemokine family classification. IL-8 ϭ interleukin-8; ENA-78 ϭ epithelial neutrophil–activating peptide 78; Gro␣ ϭ growth-related oncogene ␣; CTAP-III ϭ connective tissue activating peptide III; Nap-2 ϭ neutrophil-activating peptide 2; Mig ϭ monokine induced by interferon-␥ (IFN␥); PF4 ϭ platelet factor 4; ITAC ϭ IFN-inducible T cell ␣ chemoattractant; BCA-1 ϭ B cell activating chemokine 1; SDF-1␣ ϭ stromal cell–derived factor 1; GCP-2 ϭ granulocyte chemotactic protein 2; MCP-1 ϭ monocyte chemoattractant protein 1; LARC ϭ liver and activation-regulated chemokine; MIP-1␣ ϭ macrophage inflammatory protein 1␣; TARC ϭ thymus and activation–regulated chemokine; HCC-1 ϭ hemofiltrate CC chemokine 1; PARC ϭ pulmonary and activation-regulated chemokine; MDC ϭ macrophage-derived chemokine; MPIF-1 ϭ macrophage procoagulant-inducing factor 1; CTACK ϭ cutaneous T cell–attracting chemokine; MEC ϭ mucosae-associated epithelial chemokine; SCM-1␤ ϭ single C motif 1␤; TM ϭ transmembrane domain; Cyt ϭ cytoplasmic domain. Adapted, with permis- sion, from ref. 12. 111 C chemokines and CX3C chemokines have been RA resulted in decreased In-labeled granulocyte mi- described based on the position of cysteine residues gration into affected joints as well as a reduction in the (Figure 1) (1). The C family contains lymphotactin/ expression of IL-8/CXCL8 in the ST (26). Chemokine XCL1 and single C motif 1␤ (SCM-1␤)/XCL2, while the networks exist in the RA joint, so that RANTES/CCL5, CX3C family contains fractalkine/CX3CL1. monocyte chemoattractant protein 1 (MCP-1)/CCL2, or CXC chemokines. My group and several others SDF-1/CXCL12 up-regulates RA ST fibroblast expres- have detected IL-8/CXCL8 in high quantities in the sion of IL-8/CXCL8, indicating that chemokines can synovial fluid (SF), ST, and sera of patients with RA regulate the expression of other chemokines in the joint (17–20). Subsynovial macrophages, ST lining cells, and (27). A study by Patterson et al showed binding of endothelial cells express IL-8/CXCL8 (18,21,22). We labeled IL-8/CXCL8 to RA ST neutrophils (28). How- have shown that ST macrophages constitutively produce ever, although a main function of IL-8/CXCL8 may be to IL-8/CXCL8 (18). Unlike macrophages, ST fibroblasts recruit neutrophils, it has been increasingly difficult to require exogenous stimuli such as IL-1, tumor necrosis demonstrate an association between SF neutrophil factor ␣ (TNF␣), or lipopolysaccharide (LPS) to pro- counts and IL-8/CXCL8 levels. An alternative paradigm duce IL-8/CXCL8 (18,23). Regulation of IL-8/CXCL8 may be that a prominent function of RA joint IL-8/ production from RA ST fibroblasts appears to be con- CXCL8 is to mediate angiogenesis. Indeed, we have trolled by NF-␬B (24). Kraan et al showed that IL-8/ shown that IL-8/CXCL8 is a potent mediator of angio- CXCL8 was increased in the involved joints compared genesis in the RA joint (14,22). with the uninvolved joints of patients with RA (25). In a ENA-78/CXCL5 is a chemotactic factor for neu- study by Taylor et al, TNF␣ blockade in patients with trophils and is angiogenic (9,15,22,29). We have shown 712 KOCH that the ENA-78 levels observed in RA SF are much CXCL12 is involved in SF T cell adhesion to ICAM-1 higher than those in SF from patients with osteoarthritis (46). SDF-1/CXCL12 plays a role in CD4ϩ T cell (OA) (30). RA ST fibroblasts constitutively produce recruitment into the RA ST (49). T cells are able to ENA-78/CXCL5, and this production is augmented by migrate beneath RA ST fibroblasts in vitro, a process IL-1, TNF␣, or IL-18 (30,31). ENA-78/CXCL5 accounts termed pseudoemperipolesis. Pseudoemperipolesis may for a portion of the angiogenic activity observed in RA serve as a marker of T cell accumulation within ST (50). ST (22). Both SDF-1/CXCL12 and CXCR4 are expressed GRO␣/CXCL1 is a potent neutrophil chemoat- by CD68ϩ macrophages in the RA ST. Using a SCID tractant found in RA SF and ST (17,23,32,33). GRO␣/ mouse engrafted with human ST in vivo, Blades et al CXCL1 is inducible by TNF␣ and IL-1␤ in RA ST showed that when the graft was injected with SDF-1/ fibroblasts (33,34). GRO induces expression of intersti- CXCL12, human U937 monocytoid cells were recruited tial collagens by RA fibroblasts (32). to the ST (48). SDF-1/CXCL12 was a more potent CTAP-III/CXCL7, which is derived from human stimulus for monocyte recruitment than even the potent platelets (35), is angiogenic. CTAP-III/CXCL7 found in stimulus TNF␣. RA ST extracts induces synthesis of glycosaminoglycans SDF-1/CXCL12, despite lacking the ELR motif, and growth of RA ST fibroblasts (36). Cytokines such as promotes angiogenesis (16,51). RA ST fibroblasts pro- ␤ IL-1 , basic fibroblast growth factor, and epidermal duce SDF-1/CXCL12 under hypoxic conditions. ST growth factor synergize with CTAP-III/CXCL7 in induc- fibroblast-derived SDF-1/CXCL12 accumulates and is ing glycosaminoglycan synthesis (36). immobilized on heparin sulfate molecules of endothelial Granulocyte chemotactic protein 2 (GCP-2)/ cells, where it can promote angiogenesis and inflamma- CXCL6 was recently identified as being up-regulated in tion (52). RA plasma contains more SDF-1/CXCL12 RA ST fibroblasts exposed to Toll-like receptor 2 than does control plasma (53). SDF-1/CXCL12 accounts (TLR-2) ligands (37). Concentrations of GCP-2/CXCL6 for a portion of the angiogenic activity observed in RA were up-regulated in RA SF compared with OA SF. SF, as determined by the Matrigel plug rodent in vivo IP-10/CXCL10 is up-regulated in RA SF com- angiogenesis assay (52). pared with OA SF (38,39). IP-10/CXCL10 serum levels B cell recruitment has recently gained support as in rheumatoid factor–positive individuals were higher a potential target in RA.
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