For reprint orders, please contact: REVIEW [email protected] Chemokines in arthritis: key molecules in pathogenesis and potential therapeutic targets Frances Humby, An increasing wealth of evidence suggests an important role for chemokines and their Antonio Manzo & receptors in the pathogenesis of inflammation. In this review, the authors explore the role of Costantino Pitzalis† chemokines in inflammatory joint diseases, with particular emphasis on rheumatoid arthritis. †Author for correspondence Recent progress aimed at modulating the chemokine and chemokine receptor system for King’s College London School therapy will also be discussed. of Medicine, Guy’s, King’s College and St Thomas Hospitals, 5th Floor, Thomas Guy House, Guy’s Hospital, Rheumatoid arthritis (RA) is the most common share a tertiary structure, stabilized by four London, SE1 9RT, UK inflammatory joint disease [1], with an unknown cysteine residues that form disulfide bonds, dis- Tel.: +44 207 188 5903; etiology that results in the persistent inflamma- tinguishing them from the classical chemo- Fax: +44 207 188 5883; [email protected] tion of synovial tissue (ST) in the joints of attractant molecules (e.g., complement fragment affected patients. The synovitis that ensues peptides C3a and C5a and lipid molecules such results in cartilage and bone destruction and is as leukotriene B4 and platelet activating factor). linked with considerable morbidity [2]. Thus They have been subdivided into four families overall, RA is known to be associated with (Table 1) on the basis of the arrangement of their increased mortality [2,3]. Considerable work sug- cysteine residues. The two major subfamilies gests that an autoimmune process drives the have the cysteine residues adjacent to each other synovitis, which is characterized pathologically (cysteine-cysteine [CC] CK) or separated by one by proliferation and thickening of the lining amino acid (cysteine-x-cysteine [CXC] CK) [4]. layer, the phenomena of neoangiogenesis and a The other two families consist of first the CX3C mononuclear cell infiltrate. This includes CK, fractalkine/CX3CL1 [13], with three amino monocyte macrophages, B and T lymphocytes, acids separating the cysteine residues, and sec- dendritic cells, plasma cells (in some instances ond the cysteine (C) CK group, lympho- organized in typical lymphoid-like structures) tactin/XCL1 and SCM-1β/XCL2, with two and mast cells. The processes that result in these instead of four conserved cysteines [14] (see pathological appearances are the consequence of Table 1 for abbreviation definitions). an orchestrated action of a multitude of soluble All CKs act via seven transmembrane domain chemoattractants, in particular chemokines CK-Rs that are coupled to guanosine–tri- (CKs) and cell adhesion molecules that enable phosphate-binding proteins. The binding of a hematopoietic blood-borne cells to localize and CK to its cognate receptor can induce a wide be retained within the joint. CKs are chemo- spectrum of effects, including the arrest and tactic cytokines that play a crucial role in angio- firm adhesion of blood-borne cells on endo- genesis and leukocyte recruitment and exert thelial surfaces and transendothelial migration chemotactic activity towards a variety of cell into tissues. These events involve CKs on the types. Therefore, CKs and CK receptors surface of endothelial cells interacting with their (CK-Rs) have recently become the focus of con- cognate receptors on leukocytes triggering certed efforts to understand their mechanistic intracellular signals. This leads to integrin clus- role in the pathogenesis of inflammatory arthri- tering (increasing integrin avidity) and tis. Understanding their role and the pathways enhanced integrin affinity (through confor- involved may allow the possibility of targeting mational changes) [15], which is followed by them for therapy in RA. firm adhesion to the endothelium and leuko- Keywords: cell migration, cyte extravasation [16]. Once localized in the tis- chemokines, inflammation, Chemokines & chemokine receptors sues, the final positioning of various leukocyte lymphoid neogenesis, rheumatoid arthritis CKs are low molecular weight (8–14 Kd), struc- subsets is also driven by further gradients of turally-related, secreted or membrane-bound CKs. Therefore, CKs allow leukocytes to circu- proteins [4] that function as cell attractants. late from the bloodstream to specific organs and More than 50 human CKs have been character- move inside these tissues in a programmed fash- ized so far, along with 18 receptors [5–12]. They ion through spatial and temporal successions of 10.2217/17450816.1.1.53 © 2006 Future Medicine Ltd ISSN 1745-0816 Future Rheumatol. (2006) 1(1), 53–65 53 REVIEW – Humby, Manzo & Pitzalis CK gradients [17,18]. However, the activity of release of proteases from neutrophils and mono- CKs is not restricted simply to cell mobiliza- cytes, which potentiate inflammation [20]. CKs tion, as they can participate in cell activation, are also intimately involved in angiogenesis [21]. inducing the release of the content of Genetic analyses have shown that many CKs cytoplasmic storage granules, or by upregulating may have arisen from the reduplication of the expression of soluble- and membrane- ancestral genes [4] and many are clustered in bound molecules. Examples of the latter being certain chromosomal locations. Two main clus- the induction of the expression of ters have been recognized: CXC CKs clustering lymphotoxin (LT)β on B cells via BCA-1 at chromosome 4q12–13 and many CC CKs (BLC)/CXCL13 [19], and of the former, the located in another cluster at 17q11.2 [4]. Table 1. Human CXC, C, CC and CX3C chemokines and cognate receptors Common name ligand Systematic name Chemokine receptors C family Lymphotactin/SCM-1α/ATAC XCL1 XCR1 SCM-1β XCL2 XCR1 CC family I-309 CCL1 CCR8 MCP-1/MCAF/TDCF CCL2 CCR2 MIP-1 α/LD78α CCL3 CCR1,CCR5 LD78β CCL3L1 CCR1,CCR5 MIP-1β CCL4 CCR5 LAG-1 gene duplication CCL4L1 RANTES CCL5 CCR1, CCR3, CCR5 (C-10/MRP-2) CCL6 CCR1, CCR2, CCR3 MCP-3 CCL7 CCR1, CCR2, CCR3 MCP-2 CCL8 CCR2, CCR3,CCR5 (MIP-1γMRP-2) CCL9/CCL10 CCR1 Eotaxin CCL11 CCR3 (MCP-5) CCL12 CCR2 MCP-4 CCL13 CCR1, CCR2, CCR3 HCC-1 CCL14 CCR1,CCR5 HCC-2/lkn-1/MIP-1δ CCL15 CCR1,CCR3 HCC-4/LEC/LCC-1 CCL16 CCR1,CCR2 TARC CCL17 CCR4 DC-CK1/PARC/AMAC-1 CCL18 Unknown MIP-3β/ELC/exodus-3 CCL19 CCR7 MIP3α/LARC/exodus-1 CCL20 CCR6 6Ckine/SLC/exodus-2 CCL21 CCR7 MDC/STC-1 CCL22 CCR4 MPIF-1/CKβ8/CKβ8–1 CCL23 CCR1 Eotaxin-2/MPIF-2 CCL24 CCR3 TECK CCL25 CCR9 Eotaxin-3 CCL26 CCR3 CTACK/ILC CCL27 CCR10 MEC CCL28 CCR3/CCR10 AMAC: Alternative macrophage activation-associated chemokine; ATAC: Activation-induced T-cell-derived and chemokine-related cytokine; BCA: B-cell attracting; BLC: B lymphocyte chemokine; BRAK: Breast and kidney-expressed chemokine; C: Cysteine; CC: Cysteine-cysteine; CXC: Cysteine-x-cysteine; CTACK: Cutaneous T-cell attracting chemokine; DC: Dendritic cell; ELC: Epstein–Barr virus-induced molecule 1 ligand chemokine; ENA: Epithelial cell-derived neutrophil-activating protein; GCP: Granulocyte chemotactic protein; GRO: Growth related; HCC: Hemofiltrate cysteine-cysteine; IL: Interleukin; ILC: IL-11Ra-locus chemokine; IP: Interferon-γ inducible protein; LAG: Lymphocyte activating gene; LARC: Liver and activation-regulated chemokine; LCC: Liver CC chemokine; LEC: Liver-expressed chemokine; MCAF: Monocyte chemotactic and activating factor; MCP: Monocyte chemoattractant protein; MDC: Macrophage-derived chemokine; MEC: Mammary-enriched chemokine; MGSA: Melanoma growth stimulatory activity; Mig: Monokine induced by IFN-γ; MIP: Macrophage inflammatory protein; MPIF: Macrophage procoagulant inducing factor; MRP: Multidrug resistance-associated protein; NAP: Neutrophil activating protein; PARC: Pulmonary and activation- regulated chemokine; PF: Platelet factor; RANTES: Regulated on activation, normal T-cell-expressed and secreted; SCM: S-carboxymethyl; SDF: Stromal-cell derived factor; SLC: Secondary lymphoid organ chemokine; STC: Stem hematopoietic cells; TAC: T-cell-α chemoattractant; TARC: Thymus and activation-regulated chemokine; TDCF: Tumor-derived chemotactic factor; TECK: Thymus-expressed chemokine. 54 Future Rheumatol. (2006) 1(1) Chemokines in arthritis – REVIEW Table 1. Human CXC, C, CC and CX3C chemokines and cognate receptors (cont.). Common name ligand Systematic name Chemokine receptors CX3C family Fractalkine CX3CL1 CX3CR1 CXC chemokine/receptor family GRO-α/MGSA-α CXCL1 CXCR2 > CXCR1 GRO-β/MGSA-β CXCL2 CXCR2 GRO-γ/MGSA-γ CXCL3 CXCR2 PF4 CXCL4 Unknown ENA-78 CXCL5 CXCR2 GCP-2 CXCL6 CXCR1, CXCR2 NAP-2 CXCL7 CXCR2 IL-8 CXCL8 CXCR1, CXCR2 Mig CXCL9 CXCR3 IP-10 CXCL10 CXCR3 I-TAC CXCL11 CXCR3 SDF-1 α/β CXCL12 CXCR4 BCA-1(BLC) CXCL13 CXCR5 BRAK/bolekine CXCL14 Unknown (Lungkine) CXCL15 Unknown Small inducible cytokine B6 CXCL16 CXCR6 AMAC: Alternative macrophage activation-associated chemokine; ATAC: Activation-induced T-cell-derived and chemokine-related cytokine; BCA: B-cell attracting; BLC: B lymphocyte chemokine; BRAK: Breast and kidney-expressed chemokine; C: Cysteine; CC: Cysteine-cysteine; CXC: Cysteine-x-cysteine; CTACK: Cutaneous T-cell attracting chemokine; DC: Dendritic cell; ELC: Epstein–Barr virus-induced molecule 1 ligand chemokine; ENA: Epithelial cell-derived neutrophil-activating protein; GCP: Granulocyte chemotactic protein; GRO: Growth related; HCC: Hemofiltrate cysteine-cysteine; IL: Interleukin; ILC: IL-11Ra-locus chemokine; IP: Interferon-γ inducible protein; LAG: Lymphocyte activating