Chemokines and leukocyte trafficking in rheumatoid arthritis

Pathophysiology 13 (2006) 1–14

Chemokines and leukocyte trafficking in rheumatoid arthritis夽 Teresa K. Tarrant a , Dhavalkumar D. Patel b,∗ a

Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Thurston Arthritis Research Center, University of North Carolina, 3330 Thurston Bldg., CB#7280, Chapel Hill, NC 27599, USA b Departments of Medicine and Microbiology and Immunology, Division of Rheumatology, Allergy, and Immunology, Thurston Arthritis Research Center, University of North Carolina, 3330 Thurston Bldg., CB#7280, Chapel Hill, NC 27599, USA

Abstract Leukocyte infiltration into the joint space and tissues is an essential component of the pathogenesis of rheumatoid arthritis (RA). In this review, we will summarize the current understanding of the mechanisms of leukocyte trafficking into the synovium, focusing on the role of adhesion molecules, chemokines, and chemokine receptors in synovial autoimmune inflammation. The process by which a circulating leukocyte decides to migrate into the synovium is highly regulated and involves the capture, firm adhesion, and transmigration of cells across the endothelial monolayer. Adhesion molecules and chemokine signals function in concert to mediate this process and to organize leukocytes into distinct structures within the synovium. Chemokines play a key regulatory role in organ-specific leukocyte trafficking and activation by affecting integrin activation, chemotaxis, effector cell function, and cell survival. Consequently, chemokines, their receptors, and downstream signal transduction molecules are attractive therapeutic targets for RA. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Rheumatoid arthritis; Chemotaxis; Chemokine; Synovial; Leukocyte

1. Leukocyte migration A key step in the development of an inflammatory process, including autoimmune diseases like RA, is the recruitment of leukocytes to the site of inflammation. This involves multiple regulatory steps initially proposed in the multi-step models of Springer [1] and Butcher and co-workers [2]. This process involves: (1) leukocyte rolling; (2) rapid activation of leukocyte integrins and subsequent adhesion to endothelial ligands (firm adhesion); (3) transendothelial migration (diapedesis); and (4) migration of inflammatory cells through tissues in response to chemokine gradients. 1.1. Leukocyte capture and rolling Migration of leukocytes to sites of inflammation begins with cell capture and subsequent rolling along endothelium (Fig. 1). This initial capture of leukocytes by the endothelium is mediated primarily by cell surface proteins of the This paper was part of the Rheumatoid Special Issue, See Pathophysiology 12/3. ∗ Corresponding author. Tel.: +1 919 966 0552; fax: +1 919 966 0550. E-mail address: [email protected] (D.D. Patel). 0928-4680/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pathophys.2005.11.001

selectin family and their ligands during resting and inflammatory conditions [3]. However, other receptor-ligand interactions including CD44-hyaluronan and CX3CR1-fractalkine (CX3CL1) are effective at cell capture during specific types of inflammation [4–6]. 1.1.1. Selectins and their ligands There are three major classes of selectins that are predominantly, albeit not exclusively, expressed on the cells for which they are named. L (leukocyte)-, P (platelet)-, and E (endothelial)-selectins are also named CD62L, CD62P, and CD62E, respectively [7,8]. The selectins recognize and bind to similar carbohydrate moieties at the lectin domain during inflammation. When a cell is in the resting state, P-selectin is present internally within the ␣-granules of platelets or within WeibelPalade bodies of endothelial cells. Once activated by inflammatory or thrombogenic mediators, the granules fuse with the plasma membrane and P-selectin is expressed on the cell surface where it functions in cell adhesion [9]. Within minutes of an inflammatory signal, cell surface P-selectin is removed by proteolytic cleavage thus limiting the effective window of adhesion.

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L-selectin is expressed on all leukocytes with the exception of a subset of memory T cells [15,16], and attachment of leukocytes to the endothelium both in vivo [17,18] and in vitro [19,20] is largely L-selectin dependent. L-selectin regulation is particularly important in the organ-specific trafficking of leukocytes [21]. In L-selectin deficient animals, T cells are unable to home to peripheral lymph nodes, supporting a critical role of L-selectin in homeostatic lymphocyte trafficking [22]. L-selectin is rapidly cleaved from the cell surface after cellular activation, and may play an important role in receptor regulation and function. L-selectin shedding is not required for diapedesis or for na¨ıve lymphocyte homing and recirculation to peripheral lymph nodes [23,24]. However, inhibition of L-selectin shedding on antigen-specific lymphocytes and neutrophils alters their migratory pathways [25,24]. 1.1.2. CD44 and hyaluronan An additional capture molecule present on activated T cells is CD44 [26]. CD44 is present on most cell types, and is a member of the hyaldherin family with similar structure to the selectins [27,5]. There are several different isoforms identified, which contribute to its multifunctionality, and many are present in the inflamed joint. Upregulation of CD44 and a subsequent increase in its ability to bind to hyaluronate is likely to be functionally important in inflammatory disease states such as RA [5]. 1.1.3. Fractalkine (CX3CL1) and CX3CR1 Fractalkine is a unique molecule that functions as a chemokine in its secreted form, and as a selectin-like adhesion molecule when it is expressed on the cell surface [28,4]. Like the selectins, fractalkine can mediate the rapid capture of circulating leukocytes. Fractalkine has a mucin domain that extends from the cell surface and is structurally and functionally similar to the short consensus repeats of the endothelial expressed selectins (E- and P-selectin) [29]. Tyrosine sulfation, which enhances ligand binding between P-selectin and its ligand P-selectin glycoprotein ligand-1 (PSGL-1), is also important in fractalkine-CX3CR1 interactions that mediate leukocyte capture [30]. 1.2. Leukocyte firm adhesion

Fig. 1. Schematic depicting the current understanding of leukocyte capture and adhesion that is critical to cellular migration to sites of inflammation. Depicted are circumstances in which (A) selectins, (B) CD44 and (C) CX3CR1 participate in leukocyte capture by endothelial cells.

E-selectin is expressed on activated endothelial cells hours after exposure to inflammatory mediators such as IL-1␤, TNF-␣, interferon-␥, substance P, and LPS [10]. E-selectin is specifically upregulated on endothelial cells in inflamed synovium, and may be important in the recruitment of inflammatory cells in RA [11–14].

The types of molecular interactions involved in cell capture are generally weak and lead to leukocyte rolling on the endothelium. During the process of rolling, leukocytes are triggered by endothelial surface bound chemokines to stop and become firmly adherent to the endothelium through a process termed activation-dependent stable arrest. The firm adhesion is mediated by interactions between integrins and their ligands. Integrins are usually in an inactive state on leukocytes and become activated after the triggering of certain G protein coupled receptors like chemokine receptors [31]. Their ligands on the endothelium are members of the

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immunoglobulin superfamily known as intercellular adhesion molecules (ICAMs) as well as vascular cell adhesion molecule 1(VCAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1), and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) [32,33]. Important integrinligand interactions include the leukocyte specific ␤2 integrins, leukocyte functional antigen-1 (LFA-1, CD11a/CD18), complement receptor type-3 (CR3, CD11b/CD18, Mac-1), and p150,95 (CD11c/CD18) with their ligands ICAM-1 and -2 [9]. The ␤1 integrins, and in particular very late antigen-4 (VLA-4, CD49d/CD29), are particularly important in wound healing and cell trafficking in embryogenesis [33]. VLA-4, which is expressed on monocytes, basophils, and eosinophils in addition to T- and B-lymphoctes, interacts with its ligand VCAM-1 to induce cell adhesion [33]. When integrinligand interactions are impaired, firm adhesion and subsequent recruitment of leukocytes toward sites of inflammation is impaired. A clinical example that highlights this defect is Leukocyte Adhesion Deficiency syndrome type 1 (LAD1) [34], where individuals who are deficient in the common chain (CD18) of the ␤2 integrins have a syndrome of poor wound healing and recurrent bacterial infections. Integrin ligand expression varies on vascular endothelium and may regulate lymphocyte migration patterns. ICAM-2 (CD102) is constitutively expressed, which suggests a role in maintaining homeostatic leukocyte trafficking [35]. In contrast, ICAM-1 (CD54) is markedly upregulated in response to proinflammatory cytokines and thus, appears to be more important in inflammatory responses [36]. Integrins are not constitutively active on leukocytes, and integrin-ligand engagement requires a second signal to strengthen its interaction (i.e. activation-induced stable arrest). Signaling through the chemokine receptor in a RhoAdependent mechanism leads to a conformational change in leukocyte integrins [2,37]. As a result, ligand binding occurs with high avidity and affinity, which leads to leukocyte arrest and firm adhesion [31]. Rapid integrin-dependent adhesion then occurs through the pertussis toxin (PTX) sensitive Gi␣ subunit of a heterotrimeric GTP-binding protein [31]. Chemokines facilitate integrin binding to establish firm adhesion and differentially do so amongst different leukocyte populations. Epstein-Barr virus-induced molecule-1 (ELC, MIP-3␤, CCL19), secondary lymphoid tissue chemokine (SLC, 6-Ckine, CCL21), and stromal cell derived factor-1 (SDF-1, CXCL12) trigger rapid adhesion through ICAM1 binding of most lymphocyte populations in static and physiologic flow conditions in vitro [31], whereas liver and activation-regulated chemokine (LARC, MIP-3␣, CCL20) and monocyte chemoattractant protein (MCP-3, CCL7) specifically activate integrins on subpopulations of T lymphocytes [31,27,5]. Fractalkine (CX3CL1) has been shown to preferentially induce adhesion of different leukocyte subsets both in vitro and in vivo. Fractalkine leads to stable arrest of CD16+ monocytes [38]. In vivo fractalkine plays an important role in the recruitment and adhesion of monocytes and natural

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killer cells in a variety of immune responses such as vascular inflammation, allograft rejection and tumor clearance [39–44] and unpublished observations. Thus, by regulating firm adhesion in different leukocyte subsets, chemokines can function as control signals in cell-specific endothelial cell recognition and recruitment that may be important in inflammatory disease states. 1.3. Transendothelial migration (diapedesis) Diapedesis is the process whereby the leukocyte migrates across the endothelial monolayer and basement membrane into the tissues. It is a complex process that is poorly understood and likely involves several molecular interactions acting in concert. After transendothelial migration and extravasation into tissues occurs, the leukocyte must receive new signals, often in the form of chemokine gradients, to continue the process of recruitment toward the site of inflammation. Platelet endothelial cell adhesion molecule-1 (PECAM1, CD31) is an immunoglobulin-related molecule involved in a broad scope of biologic functions but it is felt to play a role, albeit not exclusively, in transendothelial migration. It is expressed on leukocytes as well as at the endothelial cell junctions of the monolayer. Blockage of PECAM-1 on the endothelium, monocytes, or neutrophils, inhibits leukocytes from transendothelial migration [45], and PECAM-1 blockade in animal models reduces leukocyte infiltration into inflamed tissues [46]. In rat adjuvant-induced arthritis (AIA), treatment with anti-PECAM-1 resulted in a decrease in the mean number of adherent leukocytes per 100 ␮M sized vessel within the synovium, as visualized by confocal microscopy, compared to controls [47]. In the collagen-induced arthritis (CIA) mouse model, inhibition of PECAM-1 with a monoclonal antibody ameliorated but did not abolish disease [48]. In genetically engineered animals deficient in PECAM1, neutrophils display an abnormal migration through the basal lamina; however, there are normal numbers of leukocytes recovered from sites of inflammation [49]. Surprisingly, these animals have exacerbated inflammatory arthritis in the CIA model [50]. In general, the PECAM-1 deficient animals develop spontaneous autoimmunity in that they develop autoantibodies, proteinuria, and immune complex glomerulonephritis over time [51]. The etiology of this apparent paradox is not clear, but could be explained by a functional redundancy in PECAM-1 deficient animals or a role for PECAM-1 in regulating tolerance.

2. Chemokines and chemokine receptors Chemokines are small, structurally related peptides of 8–10 kD that function to upregulate integrin adhesiveness and promote leukocyte migration into tissues [5,9]. The chemokine system is extensive with an estimated 50 chemokine ligands and 20 receptors. Chemokines are

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secreted from a wide variety of cells, and are involved in both innate and adaptive immune responses. They are similar in amino acid sequence and bind to receptors containing seven transmembrane spanning helices. They are classified based on the N-terminal structure of cysteine residues into either the C, CC, CXC, or CX3C families. The classification does not imply function, but rather to which family of receptors a chemokine binds. Consequently, most chemokines appear to have redundant specificity since they bind to numerous receptors within the same family. The two larger groups of chemokine families are the CC and CXC families. CC chemokines have adjacent cysteine residues and bind to one or several of the nine CCR receptors. Typically, these peptides are chemoattractants for monocytes, but have also been described to affect T cell, NK cell, basophil, and eosinophil migration [52]. The CXC family has one nonconserved amino acid located in between the two conserved cysteines. They serve as ligands for the six known CXCR receptors. In general, CXC chemokines with a Glu-Leu-Arg (ELR) motif located before the first cysteine promote the migration of neutrophils and angiogenesis [9,52]. Fractalkine (CX3CL1) is the only member of the CX3C family described to date, and has several unique attributes. Fractalkine is expressed on endothelial cells, and its receptor, CX3CR1, is expressed in humans on T lymphocytes, NK cells, and monocytes [28]. The chemokine domain of fractalkine is highly homologous to members of the CC chemokine family; however, fractalkine has three amino acids between the N-terminal cysteine residues [53]. More interestingly, it exists both as a secreted and a membrane-bound protein. In its membrane-tethered form on TNF-activated endothelium, fractalkine participates in the capture and firm

adhesion of leukocytes under physiologic flow conditions that is both integrin and G-protein signaling independent [4]. Chemokines signal through G protein coupled receptors (GPCRs). Signal transduction typically occurs through the PTX-sensitive Gi␣ subunit of the chemokine receptor, but other cases have been described where G protein coupling is PTX insensitive [54–56]. Receptor-ligand interaction induces a conformational change in the GPCR leading to GTP hydrolysis, release of G␣ and G␤␥ subunits that activate phospholipase C (PLC), PI3 kinase (PI3K), and receptor tyrosine kinases. Chemotaxis is dependent on activation of PI3K [57,58], whereas activation of the small GTP binding protein RhoA increases integrin adhesiveness [2,37]. Recent evidence from our group and others has shown that ␤-arrestin 2 signaling plays an important role in chemotaxis [59]. ␤-Arrestins mediate G protein receptor desensitization and endocytosis via clathrin coated pits [60]. They also serve as scaffolds involved in G-protein independent signaling pathways such as the ERK/MAPK pathway [61–63] (Fig. 2). The downstream pathways of ␤-arrestin 2 activation that result in chemotaxis are still unclear, but splenocytes isolated from animals deficient in either ␤-arrestin 2 or G protein coupled receptor kinase 6 (GRK6) have markedly impaired chemotactic responses to SDF-1 [59]. In vivo, ␤arrestin 2 deficient animals have diminished hyper-airway responsiveness in a murine model of allergic asthma, and have diminished CD4+ T cells within the airways, likely due to a defect in trafficking [64]. Chemokines are either constitutively expressed or induced during inflammation. In general, the constitutive chemokines such as ELC and SLC act on na¨ıve lymphocytes where their receptors, CXCR5 and CCR7, are expressed [65]. This is in contrast to macrophage inflammatory protein-

Fig. 2. Signal transduction pathways through chemokine receptors. Classic heterotrimeric G-protein dependent pathways are activated by chemokine agonists and lead to cellular responses via activation of PI3K dependent pathways. Agonist activation also leads to GRK-mediated phosphorylation of the chemokine receptor tail, and binding of b-arrestin. b-arrestin binding not only leads to receptor desensitization to further G-protein mediated signals, but also serves to activate new signaling pathways, possibly leading to different cellular responses.

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1␤ (MIP-1␤, CCL4), regulated upon activation normal T cell expressed and secreted (RANTES, CCL5), monokine induced by interferon-␥ (Mig, CXCL9), eotaxin (CCL11), and IP-10 (CXCL10) chemokines, which are upregulated in inflammatory tissues and target specific leukocyte subsets [66]. Chemokines and their receptors differentially recruit Th1 versus Th2 subsets. In general, CXCR3 and CCR5 are predominantly expressed on Th1 cells and monocytes, whereas CCR3 and CCR4 are differentially expressed on Th2 cells [67]. Antibody blockade of CXCR3, which is upregulated in rheumatoid arthritis and is the receptor for inflammatory chemokines such as IP-10, MIG, and IFNinducible T cell ␣ chemoattractant (I-TAC), inhibits recruitment of Th1 cells in an adjuvant-induced peritonitis model [68]. Thus, chemokines maintain normal homeostatic migration of leukocytes in addition to participating in both innate and adaptive immune responses. Chemokines have been appreciated as playing a major role in organ-specific trafficking since the landmark finding that a defect in CXCR5 led to defective migration of B cells to the spleen and Peyer’s patches [69]. B cell attracting chemokine 1 (BCA-1, CXCL13), SDF-1 (CXCL12), ELC (CCL19), and SLC (CCL21) have been identified as being constitutively expressed in normal lymphoid tissues and are responsible for the homeostatic trafficking and eventual positioning of B-, T-, and dendritic cells within these structures [69–73]. Lymphoid aggregates with formations similar to germinal centers are seen within the inflamed rheumatoid synovium and are discussed in further detail below. Targeting these regulation pathways within different tissues could potentially treat autoimmune inflammatory disease states without the need for global immunosuppressive therapy. 3. Regulation of leukocyte trafficking to inflamed synovium Organ-specific leukocyte trafficking can occur at many different points and is highly regulated. Increased cell recruitment occurs by upregulating selectin or integrin adhesion molecule expression on the cell surface or by increasing leukocyte migration and activation through differential chemokine production. The resulting infiltrate consists of many leukocyte subsets including granulocytes, T cells, B cells, monocytes, macrophages, dendritic cells and mast cells, each contributing in unique ways to the inflammation. Subsets of leukocytes may also be retained for sustained periods of time within inflamed tissues. When one or several of these regulatory mechanisms become altered, the result can lead to chronic inflammation or autoimmunity such as in RA. Table 1 summarizes the roles in inflammatory arthritis of some of the molecules involved in leukocyte trafficking. 3.1. Adhesion molecules and rheumatoid arthritis There is accumulating evidence that leukocyte trafficking to the inflamed synovium in RA is adhesion molecule depen-

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dent. E-selectin expression is upregulated in the inflamed synovium, and subsequently decreases in disease remission after TNF-␣ blocking therapy [14]. Serum levels of both Land P-selectin are increased in RA patients [74], but only Pselectin levels correlate with disease activity [5,75]. In the rat adjuvant-induced arthritis (AIA) model, blocking antibodies to P-selectin inhibited the accumulation of neutrophils and monocytes [76]. However, P-selectin deficient mice develop a more severe form of collagen-induced arthritis (CIA), which demonstrates that inflammatory arthritis is not entirely Pselectin dependent [77]. CD44 is upregulated in RA patients [6,78], and may be important in disease pathogenesis. In humans, inflammatory arthritis disease activity correlates with the ability of antigen-specific T cells to roll on hyaluronic acid, a ligand for CD44 [5]. Blocking antibodies to the CD44-ligand interaction inhibit leukocyte trafficking in mouse models of arthritis [79] and decrease in vitro migration of synovial-like fibroblasts [80]. The role of CD44 in synovitis is pleotropic since cross-linking CD44 on RA synovial cells in vitro up regulates Fas (CD95)-expression, and both hyaluronan fragments and CD44 engagement stimulate early Fas-mediated apoptosis of RA synovial cells in vitro [81]. Spontaneous growth arrest and remission are observed in RA synovial cells that express functional Fas antigens in addition to frank apoptosis [81,82]. This imbalance between cell proliferation and cell death, mediated by CD44 interactions, could contribute to the pathological process of synovitis in RA. The role of integrins in organ-specific leukocyte homing to the RA synovium is less clear. Blocking the different classes of integrins does not inhibit leukocyte binding to the vascular endothelium in RA synovium in vitro [5], and anti-LFA-1 antibodies do not inhibit T lymphocyte or neutrophil migration in AIA [83]. Although VCAM-1 is upregulated in RA synovium and soluble levels correlate with clinical severity (reviewed in [84]), VCAM-1 blockade does not dramatically reduce inflammatory cell migration into arthritic joints or prevent disease in CIA [85]. However, combined anti-LFA-1 and anti-VLA-4 blockade inhibits monocyte migration to the inflamed synovium [86], and ICAM-1 (CD54) deficient mice have decreased disease expression in CIA [87]. One potential mechanism for integrin-mediated regulation in RA is at the level of the synoviocyte as opposed to the leukocyte. Interaction of ␤1 integrins with ICAM-1 and Fas antigen on RA synovial cells induces Fas-mediated apoptosis [82]. This pathway could potentially lead to the spontaneous growth arrest and dysregulation of synoviocytes seen in inflammatory RA. 3.2. Chemokines and chemokine receptors in rheumatoid arthritis Chemokines and their receptors are key players in the recruitment of inflammatory cells to the synovium in RA. Numerous chemokines have been found to be expressed at both the protein and mRNA level in the inflamed synovial

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Table 1 Properties of selected molecules in RA that affect leukocyte trafficking and recruitment Molecule

Family

Names

Function

Selectins CD62E

Selectin

Leukocyte rolling.

CD62L

Selectin

E-selectin, ELAM-1, LECAM-2 L-selectin, LAM-1, LECAM-1, Leu-8

CD62P

Selectin

P-selectin, PADGEM, GMP-140

Leukocyte rolling.

(1) Blockade inhibits neutrophil/monocyte accumulation in AIA. (2) Blockade ameliorates CIA. (3) CD62P deficient animals have increased CIA.

Integrin

LFA-1

Firm adhesion.

Blockade does not alter leukocyte migration.

Ig family

PECAM-1, GpIIa, EndoCAM

Diapedesis.

(1) Blockade ameliorates CIA and AIA. (2) CD31 deficient animals have increased CIA and enhanced autoimmnity.

CD31

Upregulated in RA, levels decrease after anti-TNF␣ treatment. Levels are not consistent with RA flares.

Leukocyte rolling.

Immunoregulation?

Human data in RA

Increased in RA, correlates with disease activity.

CD44

Hyaldherin

H-CAM, Pgp-1, Hermes, In(Lu)-related

Lymphocyte rolling, cell adhesion.

(1) Blockade decreases leukocyte trafficking in rodent models of RA. (2) Increased Fas expression and apoptosis of synoviocytes after cross-linking CD44 in vitro.

(1) Numerous isoforms present in inflamed joint. (2) Present in inflamed synovium.

CD54

Ig family

ICAM-1

Firm adhesion of leukocytes.

(1) CD54 deficient animals have reduced CIA.

(1) Randomized, placebo controlled trial with inhibitor could not demonstrate efficacy.

(2) Fas mediated synoviocyte apoptosis in vitro. CD106

Ig family

VCAM-1, INCAM-110

Firm adhesion.

(1) Blockade ameliorates CIA.

(1) Increased in inflamed synovium. (2) Levels correlate with clinical disease severity.

Chemokines CCL3

CC

MIP-1␣

Th1 chemoattractant. Ligand for CCR1, 3, 5.

(1) Blockade ameliorates CIA. (2) Polyclonal antibody blockade does not improve AIA.

Elevated in RA synovial fluid.

CCL5

CC

RANTES

Chemoattractant for monocytes, Th memory cells, and eosinophils. Ligand for CCR1, 3, 4, 5.

(1) Polyclonal antibody blockade ameliorates AIA. (2) MetRANTES ameliorates CIA.

(1) Produced by RA synoviocytes in response to proinflammatory cytokines. (2) Levels similar to patients with OA.

CXCL13

CXC

BCA-1

Lymphocyte homing, germinal center formation.

CX3CL1

CX3C

Fractalkine, neurotactin

Integrin independent leukocyte capture and firm adhesion.

May contribute to organized lymphoid aggregates in RA synovium. Blockade ameliorates CIA.

Receptor CX3CR1 increased on circulating and residing T cells in RA.

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Adhesion molecules CD11a/CD18

Animal data in arthritis

Table 1 (Continued) Molecule

Family

CCR2

CCR5

CCR

CCR

Function

Animal data in arthritis

Present on monocytes, immature dendritic cells, T cells, basophils. Present on monocytes, immature dendritic cells, basophils, T cells, particularly Th2.

Present on monocytes, immature dendritic cells, T cells, Th1 cells.

Human data in RA Phase IIb study of CCR1 inhibitor demonstrated safety and trend toward improvement.

CCR2 deficient animals have increased CIA.

(1) Ligand MCP-1 upregulated by activated synoviocytes with TNF-␣.

Blockade ameliorates CIA.

(2) Tissue infiltrating monocytes have increased CCR2.

CCR5 deficient animals have similar CIA scores as controls.

(1) Upregulated in RA. (2) Polymorphism
32 associated with milder disease. (3) Ligands MIP-1␣, MIP-1␤, RANTES elevated in RA.

CXCR3

CXCR

Present on activated T cells, particularly Th1.

(1) Upreguated in RA. (2) Ligands IP-10, Mig elevated in RA.

CXCR4

CXCR

Present on basophils, Th2 cells, and mature dendritic cells.

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Chemokine receptors CCR1 CCR

Names

Blockade ameliorates CIA.

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fluid, which mirrors the diverse inflammatory cellular infiltrate histopathologically [88]. In particular, Th1 chemoattractants such as MIP-1␣, MIP-1␤, IP-10 and Mig and their receptors CCR5 and CXCR3 are upregulated within the synovial microenvironment [89,88]. CCR2 and CCR5 are expressed on T cells and macrophages within the inflamed joints of RA patients [90–92] and in CIA in animals [93]. RA patients also have increased CX3CR1 expression on circulating and synovial-residing T cells that produce Th1-type cytokines [94,95]. IL-8 (CXCL8) and ENA-78 (epithelialneutrophil activating protein 78, CXCL5), which attract neutrophils and monocytes, and MCP-1 (monocyte chemoattractant protein 1, CCL2), which attracts monocytes, are secreted by activated synovial fibroblasts in response to proinflammatory cytokines such as TNF-␣ [88,5,96]. The sources of chemokines are both the synovial lining cells as well as infiltrating leukocytes [97]. Although macrophage-lymphocyte chemokines are elevated, the data do not entirely support a pathogenic role. MIP1␣, which is expressed by synovial macrophages, is elevated in RA synovial fluid [98], but MIP-1␤ is variably elevated in RA when compared to synovial fluid from osteoarthritis (OA) patients [99]. Although RANTES mRNA is induced in response to proinflammatory cytokines by RA synovial fibroblasts, RANTES protein levels are similar between RA and OA patients [100]. The microenvironment within the chronically inflamed joint may also retain and compartmentalize pathogenic cells through chemokine interactions, and there is accumulating evidence to suggest that the SDF-1 interaction with its receptor CXCR4 may play a role in the inflammatory process [101]. TGF-␤ upregulates CXCR4 expression on synovial T cells, which then functionally adhere to both ICAM-1 and fibronectin after exposure to SDF-1 [102]. Cultured synovial fibroblasts from RA patients express high levels of SDF1 and VCAM-1, but only the SDF-1/CXCR4 interactions affect T cell migration in vitro [103]. T cell subsets displayed specific patterns and rates of migration in co-culture with synovial fibroblasts, suggesting that SDF-1/CXCR4 interactions may contribute to the compartmentalization of CD4+ versus CD8+ inflammatory T lymphocytes in RA [103,101]. CXCR4/SDF-1 interaction also protects T cells from undergoing activation-induced cell death, which may lead to accumulation of inflammatory effector cells within the joint space [104]. Approximately 20% of RA patients have B and T lymphocyte aggregates beneath the synovial lining with a similar organization to germinal centers [105]. CXCL13, whose expression is primarily confined to B cell follicles, has also been identified in the RA synovium and may participate in the establishment of these structures [106–108]. Two groups identified that CXCL13 was primarily expressed in germinal centers within lymphoid aggregates, which was dependent on the presence of follicular dendritic cells [107,108]. In addition, the Takemura group found CXCL13 expression within endothelial cells of small arterioles and capillaries,

which suggests that it could be functioning in recruitment as well as maintenance of these organized lymphoid structures [106,107]. Evaluation of chemokine receptor expression in RA has yielded some intriguing observations. Epidemiologic studies have suggested that the CCR5
32 polymorphism, which results in a defective receptor, may confer milder disease in patients with RA [109], but this correlation has not been consistently confirmed [110]. The chemokine receptors most abundantly expressed on activated leukocytes in RA patients are CCR5 and CXCR3 [88,89], and CCR2 on tissue infiltrating monocytes [111]. However, the genetic deletion of CCR5 in the murine CIA and collagen-Ab-induced arthritis (CAIA) models showed no difference in disease expression compared to wild-type controls [111]. This result highlights the redundancy of the chemokine system, and how targeting one molecule may not be therapeutically efficacious. Earlier animal work in either CCR2 deficient mice or in mice treated with a monoclonal antibody to CCR2 (MC21) showed a pronounced defect in leukocyte migration [112,113]. However, CCR2 deficient animals immunized to develop CIA had a more accelerated and severe form of inflammatory arthritis as well as increased autoantibody production compared to controls [113]. Further mechanistic studies elucidated that early (days 0–15) versus late (days 21–36) blockade of CCR2 with MC-21 antibody could produce different phenotypes of protected versus exacerbated arthritis in the CIA model [114]. This study identified a subpopulation of CCR2+/CD25+ regulatory T cells, which were anergic to collagen-specific activation [114]. These results suggest that the regulatory control of lymphocyte trafficking is highly complex and could even lead to enhanced autoimmunity when the regulatory balance is tipped in certain disease states. Given the observation that synovial macrophages express high levels of CCR2 in inflammatory arthritis and that macrophages are still present in the inflamed joint despite CCR2 deletion [111], the role of the monocyte/macrophage in disease pathogenesis continues to be an actively explored area. A new paradigm has been suggested by the Littman group that describes monocyte/macrophage subsets based on CCR2 and CX3CR1 expression and their relative roles in inflammation [115]. In this model, circulating peripheral blood monocytes that are CX3CR1lo /CCR2+/Gr1+ in mice (CD14+/CD16− in humans) are actively recruited to inflammatory sites whereas CX3CR1hi /CCR2-/Gr1− resident macrophages (CD14lo /CD16+ in humans) predominate in non-inflamed tissues [115]. This polarization of monocyte/macrophage subsets and their role in RA needs to be further studied.

4. Therapeutic considerations Inhibitors to adhesion molecules have had some success in animal models of inflammatory arthritis. A P-selectin

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glycoprotein ligand (rPSGL-1Ig) fusion protein was able to ameliorate established CIA in mice, partially through decreased production of TNF-␣ [116]. VCAM-1 blockade with neutralizing antibodies increases circulating B cells and is able to reduce clinical severity but not incidence of CIA [85]. A recently generated monoether derivative of probucil, compound 4ad (AGIX-4207), which has been shown to have potent inhibitory effects on VCAM-1, inhibited paw edema in a collagen II sensitized rat model and is currently in clinical trials for RA [117]. The ␤2 integrins and ICAM-1 (CD54) have been downregulated both directly and indirectly by therapeutic interventions in patients with inflammatory arthritis. Methotrexate and leflunomide, which are disease modifying antirheumatic drugs (DMARDs), downregulate the expression of ICAM-1 and VCAM-1 in the synovial tissue of patients with active RA [118,33]. Anti-ICAM-1 monoclonal antibodies have had limited success in patients with refractory RA, but did show alterations in T cell recruitment and responsiveness [119]. Consequently, a follow-up phase I/II study was performed in early RA patients where a single course of therapy was associated with clinical improvement to a greater extent than previously had been observed in patients with longstanding, aggressive RA [120]. However, a randomized, placebo controlled trial of an antisense oligodeoxynucleotide ICAM-1 inhibitor could not demonstrate clinical efficacy beyond that of placebo in the 43 patients with active RA who were studied [121]. Efazulimab, a humanized monoclonal antibody against the ␣L integrin, showed no therapeutic benefit in RA, but did show clinical efficacy in decreasing skin plaques in psoriasis [122]. Natalizumab, a monoclonal antibody against ␣4 integrins (CD49d), is in phase III clinical trials for inflammatory bowel disease and multiple sclerosis, and may have clinical benefit in RA [122]. Alefacept, anti-(LFA)-2, has been shown to be efficacious in a limited number of patients with psoriatic arthritis [123], and also may prove to be of benefit in RA. Chemokine inhibition in RA can be achieved either directly or indirectly. Neutralizing TNF-␣ and IL-1 with currently available biologic agents downregulates inflammatory chemokine and chemokine receptor expression in the synovial joint. Infliximab, a monoclonal antibody directed against TNF-␣, decreases IL-8 and MCP-1 expression in the synovium, which correlates with a decreased leukocyte infiltrate and clinical improvement [96]. Therapies targeted at the chemokine-receptor interaction have had some pre-clinical success in animal models of RA. Anti-MIP-1␣ and MIP-1␤ antibodies decreased but did not prevent disease in CIA [124]. MetRANTES, which blocks the CCR1, CCR3, CCR4, and CCR5 receptors, also ameliorated disease in the CIA model [125]. Targeting MCP-1 either by using an antagonist protein [126] or neutralizing antibodies [127], decreases inflammatory arthritis in rodent models. Inhibition of the SDF-1/CXCR4 interaction improved CIA in mice [128] as does inhibition of fractalkine [129]. Providing an insight to potential mechanism, anti-fractalkine antibody

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treatment of CIA does not alter anti-type II collagen antibody production or IFN-␥ production by stimulated effector T cells in vitro [129]. Humoral and cell mediated immune responses were left intact, but the infiltration of adoptively transferred splenic macrophages to the inflamed synovium was impaired [129]. These data suggest that cell migration could be an important target in the pathogenesis and treatment of RA. Due to the considerable redundancy of chemokine function and promiscuity within chemokine families using shared receptors, targeting one specific chemokine-receptor pair may not be effective. Consequently, small molecule inhibitors of the GPCR are being developed for possible therapeutic use. Already reported are compounds that inhibit CCR1, CCR2, CCR3, CCR5, CXCR2 and CXCR4 [130–134], and clinical trials in human disease with these compounds are forthcoming. Results from the inhibition of CCR1 in a double blind, placebo controlled, phase IIb clinical trial has recently been reported in RA [135]. In 16 randomized patients with active RA on day 15 after treatment, there was decreased cellularity of infiltrating macrophages and T cells within the synovium of the patients treated with the CCR1 antagonist. No major adverse effects were reported, and there was a trend toward clinical improvement in the patients treated with active drug [135]. Limitations of this study include small sample size and short-term follow-up. Although the data are encouraging to proceed with small molecule inhibitors targeted at the chemokine-receptor interaction, there are potential pitfalls to be considered. The first is the risk of immunosuppression and a decreased threshold for infection. CCR1 and CCR2 deficient mice have shown increased susceptibility to Toxoplasma gondii infection compared to controls [136,137], and the CCR1 deficient animals had increased mortality [137]. There is also the potential to exacerbate autoimmune disease with chemokine receptor inhibitors as illustrated by the worsening CIA in the CCR2 deficient animals [111]. The result does not appear to be isolated to Th1-mediated diseases since exacerbation is also seen in the OVA challenged allergic asthma model in CCR2 deficient mice [138]. Finally, animal studies using small molecule inhibitors to further investigate mechanism and safety may be limited secondary to species specificity and lack of cross reactivity. In addition, studies with genetically deficient animals may not be as informative as inhibiting interactions with exogenous substances like small molecule inhibitors. For example, murine CCR2 inhibitors are very effective at blocking CIA, while CCR2 deficient animals have exacerbated CIA. Recent intriguing data suggest that specific ligand interaction with a GPCR can activate non-classical ␤-arrestin signaling pathways leading to downstream effects such as chemotaxis [139]. If these data generalize to chemokine GPCRs, arguably different chemokines binding to the same receptor may activate separate signaling pathways. Therefore, small molecule inhibitors of chemokine receptors could inhibit

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classical GPCR pathways but also activate non-classical pathways leading to lack of efficacy or unexpected side effects. Further study will need to be conducted to better understand the underlying mechanisms of these complex regulatory pathways.

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5. Conclusions

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Although anti-TNF-␣ therapies have provided considerable benefit to numerous patients with RA, there are still those who obtain only partial benefit or are unable to tolerate these drugs. Consequently, there is still a need for additional therapies that can be used either in conjunction with anti-TNF-␣ drugs or to act as solo agents. Leukocyte trafficking to sites of inflammation is a highly regulated process and may be a potential therapeutic target in chronic autoimmune diseases like RA. Adhesion molecules as well as chemokine-receptor interactions that regulate organ-specific migration are ideal targets to downregulate the inflammatory response without compromising immune surveillance against infection. Designing therapies aimed at multiple chemokine receptors will likely be more effective than inhibition of a single GPCR due to the considerable redundancy and overlap of function within chemokine families.

[13]

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[16]

[17]

[18]

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