Báo cáo khoa học: Molecular aspects of rheumatoid arthritis: chemokines in the joints of patients

M I N I R E V I E W

Molecular aspects of rheumatoid arthritis: chemokines in the joints of patients Takuji Iwamoto1,2, Hiroshi Okamoto1, Yoshiaki Toyama2 and Shigeki Momohara1

1 Institute of Rheumatology, Tokyo Women’s Medical University, Japan 2 Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan

Keywords chemokine receptors; chemokines; monocyte chemoattractant protein-4 (MCP-4) ⁄ CCL13; pulmonary and activation- regulated chemokine (PARC)/CCL18; rheumatoid arthritis (RA)

Correspondence H. Okamoto, Institute of Rheumatology, Tokyo Women’s Medical University, 10-22 Kawada-cho, Shinjuku, Tokyo 162-0054, Japan Fax: +81 3 5269 1726 Tel: +81 3 5269 1725 E-mail: hokamoto@ior.twmu.ac.jp

(Received 14 March 2008, revised 27 May 2008, accepted 27 June 2008)

doi:10.1111/j.1742-4658.2008.06580.x

Rheumatoid arthritis (RA) is a chronic symmetric polyarticular joint dis- ease that primarily affects the small joints of the hands and feet. The inflammatory process is characterized by infiltration of inflammatory cells into the joints, leading to proliferation of synoviocytes and destruction of cartilage and bone. In RA synovial tissue, the infiltrating cells such as macrophages, T cells, B cells and dendritic cells play important role in the pathogenesis of RA. Migration of leukocytes into the synovium is a regu- involving interactions between leukocytes and lated multi-step process, endothelial cells, cellular adhesion molecules, as well as chemokines and chemokine receptors. Chemokines are small, chemoattractant cytokines which play key roles in the accumulation of inflammatory cells at the site of inflammation. It is known that synovial tissue and synovial fluid from RA patients contain increased concentrations of several chemokines, such as monocyte chemoattractant protein-4 (MCP-4) ⁄ CCL13, pulmonary and (PARC) ⁄ CCL18, monokine activation-regulated induced chemokine stromal cell-derived factor 1 (SDF-1) ⁄ by interferon-c (Mig) ⁄ CXCL9, CXCL12, monocyte chemotactic protein 1 (MCP-1) ⁄ CCL2, macrophage inflammatory protein 1a (MIP-1a) ⁄ CCL3, and Fractalkine ⁄ CXC3CL1. Therefore, chemokines and chemokine-receptors are considered to be important molecules in RA pathology.

Introduction

dendritic cells and natural killer cells [1]. Migration of leukocytes into the synovium is a regulated multistep process involving interactions between leukocytes and endothelial cells and cellular adhesion molecules, as well as between leukocytes and chemokines and chemokine receptors [2]. Chemokines are small, chemoattractant cytokines that play key roles in the accumulation of inflammatory cells at the site of inflammation. There- fore, chemokines and chemokine receptors are consid- in several chronic ered to be therapeutic targets

Rheumatoid arthritis (RA) is a chronic systemic inflam- matory disease that occurs in about 1% of the popula- tion. The inflammatory process is characterized by infiltration of inflammatory cells into the joints, leading to the proliferation of fibroblast-like synoviocytes (FLS) and the destruction of cartilage and bone. In RA syno- vial tissue, the infiltrating cells consist of macrophages, T cells, B cells, plasma cells, neutrophils, mast cells,

Abbreviations CCL3L1, CCL3-like 1; GROa, growth-related oncogene a; IFN-c, interferon-c; IL, interleukin; IP-10, interferon-c-inducible protein-10; MAPK, mitogen-activated protein kinase; MCP, monocyte chemoattractant protein; Mig, monokine induced by interferon-c; MIP, macrophage inflammatory protein; MMP, matrix metalloproteinase; OA, osteoarthritis; PARC, pulmonary and activation-regulated chemokine; RA, rheumatoid arthritis; RANTES, regulated on activation, normal, T-cell expressed, and secreted; SDF, stromal cell-derived factor; TNF-a, tumor necrosis factor-a.

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Chemokines in the joints of patients

Table 1. Chemokines and chemokine receptors expressed in the joint of RA patients.

inflammatory disorders such as RA. Based on a number of recently published studies, this review focuses on the chemokines expressed in RA synovial tissues.

Common name

Systemic name

Chemokine receptors

Chemokines

CC chemokines

CCL2 CCL3 CCL5 CCL13 CCL18 CCL20

CCR2 CCR1, CCR5 CCR1, CCR3, CCR5 CCR2, CCR3 Unknown CCR6

MCP-1 MIP-1a RANTES MCP-4 PARC MIP-3a

CXC chemokines

GROa IL-8 Mig IP-10 SDF-1

CXCR2 CXCR1, CXCR2 CXCR3 CXCR3 CXCR4

CXCL1 CXCL8 CXCL9 CXCL10 CXCL12 C chemokine

XCL1

Lymphotactin

XCR1

CX3C chemokine

subclasses

CX3CL1

Fractalkine

CX3CR1

[4]. Lymphotactin,

tumor necrosis

IL-1b,

(Table 1) [9,10]. The inflammatory cells that infiltrate into RA synovial tissue express chemokine receptors, including CXCR3, CCR5, CCR3, CCR2 and CXCR2 [11]. Based on these data, the chemokine system is considered to be implicated in RA pathogenesis via the recruitment and retention of monocytes and T lympho- cytes into the joints [9,12]. Although macrophages and FLS are considered to be the most potent producers of chemokines in the synovial compartment, chondrocytes also have the ability to produce chemokines [13–16]. Chemokine production is known to be induced at high levels in response to inflammatory stimuli, such as factor-a lipopolysaccharide, (TNF-a) and interferon-c (IFN-c) (Fig. 1).

Chemokine expression in the RA joint

In humans there are more than 50 types of chemokines – small (8–10 kDa) heparin-binding proteins – that were originally identified by their chemotactic activity on bone marrow-derived cells [3]. They are classified into four families according to the location of cysteine residues. The four chemokine groups are CC, C, CXC and CX3C, where C is a cysteine and X any amino- acid residue, and their receptors are consequently clas- sified as CCR, CR, CXCR and CX3CR. The chemokine receptors are bound to the cell membrane through seven transmembrane helical segments coupled to a G-protein that transduces the intracellular signal. The two major include the CC chemokines (where the cysteines are neighboring) and the CXC chemokines (where the cysteines are separated by one amino acid). The CXC chemokines mainly act on neu- trophils and lymphocytes, whereas the CC chemokines mainly act on monocytes and lymphocytes without affecting neutrophils in the C chemokine family, is similar to members of both the CC and CXC chemokine families, but lacks two of the four cysteine residues and is a potent attractant for T cells, but not for monocytes or neutrophils [5]. Frac- is a cell-surface-bound talkine, in the CX3C family, protein, in which the first two cysteine residues are separated by three amino acids, and has potent chemo- attractant activity for T cells and monocytes [6]. One characteristic feature of chemokines is the redundancy of the system. Several chemokines bind to more than one receptor, and the majority of chemokine receptors have multiple ligands, leading to the generation of multiple pathways directing similar cellular responses.

a function,

the nomenclature of

the

Until recently, chemokines have been named ran- domly, with no clear system being used. Some have been included with the interleukins [for example, inter- leukin (IL)-8], and others have been given names example, macrophage for describing chemoattractant proteins. In an attempt to clarify the confused and complex nomenclature associated with chemokines, chemokine system has been revised. The name referring to a specific biologic function has been replaced by the chemokine subfamily name followed by a number [for example, monocyte chemoattractant protein (MCP)-1 is CCL2] [7,8].

Synovial tissue and synovial fluid from RA patients contain increased concentrations of several chemokines

CC chemokines Monocyte chemoattractant protein-1 ⁄ CCL2 (a ligand of CCR2) can attract monocytes, T cells, natural killer cells and basophils [17,18]. Monocyte chemoattractant protein-1 ⁄ CCL2 is highly expressed in synovial tissue and synovial fluid in RA patients, and synovial tissue macrophages are the dominant source of MCP-1 ⁄ CCL2 production [19]. The levels of MCP-1 ⁄ CCL2 correlate significantly with the levels of IL-1b, IL-6 and IL-8 ⁄ CXCL8 in culture supernatants of synovium from RA patients, and the expression of MCP-1 ⁄ CCL2 mRNA by cultured synovial cells is stimulated by IL-1b and TNF-a [20]. We recently found that angiotensin II activated nuclear factor-jB in FLS to induce MCP-1 ⁄ CCL2 [21].

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Chemokines in the joints of patients

A

RA joint

joints

reveals

TNF-α, IL-1β, IFN-γ

secreted from normal T cells that are regulated upon activation. Histological examination of affected rheu- matoid extensive RANTES ⁄ CCL5 expression in the synovial lining and sublining layers [22]. The expression of RANTES ⁄ CCL5 in cultured FLS increases in both a time-dependent and dose- dependent manner upon stimulation with TNF-a and IL-1b [23].

Synoviocytes

Macrophage

T cell

Chemokines

Cartilage

B

RA joint

Macrophage inflammatory protein (MIP)-1a ⁄ CCL3 (a ligand of CCR1 and CCR5) levels are higher in RA synovial fluid than in synovial fluid from other forms of arthritis, including osteoarthritis (OA). Isolated FLS produce MIP-1a ⁄ CCL3 mRNA and protein upon incubation with lipopolysaccharide and TNF-a [24]. Freshly isolated synovial fluid neutrophils also contain higher concentrations of MIP-1a ⁄ CCL3 protein than peripheral blood neutrophils from either RA patients or healthy controls, and incubation in the presence of TNF-a results in an increase in MIP-1a ⁄ CCL3 secretion by neutrophils in the synovial fluid of RA patients [25].

Macrophage

Chemotaxis

Chemokines

Synovial hyperplasia Angiogenesis

MMP release Pannus formation

inflammatory protein-3a ⁄ CCL20 (a ligand of CCR6) is a selective chemoattractant for leucocytes such as memory T cells, naive B cells and immature dendritic cells. Macrophage inflammatory protein-3a ⁄ CCL20 is highly expressed in synovial flu- ids and synovial tissue specimens of patients with RA, and cultured FLS derived from either RA or OA patients are capable of producing MIP-3a ⁄ CCL20 in response to IL-1b and TNF-a in vitro [26]. Increased expression of MIP-3a ⁄ CCL20 and CCR6 has also been confirmed in tissue biopsies from RA subchondral bone [27].

Cartilage

Our group recently found that

In addition to functioning in cell

the mRNA exp- ression of MCP-4 ⁄ CCL13 (a ligand of CCR2 and CCR3), which is the major chemoattractant for eosin- ophils, monocytes and T lymphocytes, is significantly higher in cartilage from RA patients than in cartilage from OA patients or normal controls. Furthermore, the concentration of MCP-4 ⁄ CCL13 protein in syno- vial fluid is also significantly higher in RA patients than in OA patients [28]. Monocyte chemoattractant protein-4 ⁄ CCL13 production in cultured human chon- drocytes is stimulated by IFN-c in combination with IL-1b or TNF-a [13].

Fig. 1. Schematic representation of the role of chemokines in the joint of RA patients. (A) Synovial macrophages, T cells, synovio- cytes and also chondrocytes produce various chemokines stimu- lated mainly by inflammatory cytokines, including IL-1b, TNF-a and IFN-c. (B) Chemokines expressed in the joint recruit leukocytes into the joints. trafficking, several chemokines have other biological abilities. Chemokines stimulate FLS and chondrocytes to release inflammatory mediators, including cytokines and MMPs, leading to cartilage degradation and pannus formation. Furthermore, chemokines enhance cell proliferation and angiogenesis, leading to synovial hyperplasia. Chemokines released by leukocytes and FLS, or by the chondrocytes themselves, can leading to induce autocrine ⁄ paracrine stimulation of these cells, joint destruction.

Regulated on activation, normal, T-cell expressed, and secreted (RANTES) ⁄ CCL5 (a ligand of CCR1, CCR3 and CCR5) is another CC chemokine, impli- cated in RA pathogenesis, which is expressed and

We also found that pulmonary and activation-regu- lated chemokine (PARC) ⁄ CCL18 is expressed more strongly in RA cartilage and synovial membrane than in OA samples. The levels of PARC ⁄ CCL18 in serum and synovial fluid are also higher in RA patients than in OA patients and normal controls. In addition, the levels of PARC ⁄ CCL18 in serum significantly correlate with the levels of rheumatoid factor [14].

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C and CX3C chemokines

CXC chemokines

(a

ligand of CXCR1

and

(lymphotactin ⁄ XCL1

[30].

Interleukin-8 ⁄ CXCL8

IL-8 ⁄ CXCL8

The C chemokine family is represented by two chemo- kines SCM-1b ⁄ XCL2), whereas the CX3C chemokine family contains only one member, called fractalkine ⁄ CX3CL1 [41]. The levels of lymphotactin ⁄ XCL1 are significantly higher in synovial fluid of RA patients than those in paired serum samples. Expression of XCR1, a lymphotactin ⁄ XCL1 receptor, was detected in infiltrating mono- nuclear cells and FLS of synovial tissues [42].

induction of

is

IL-8 ⁄ CXCL8

Interleukin-8 ⁄ CXCL8 and CXCR2) was the first chemokine identified to be involved in leukocyte chemotaxis [29]. Interleukin-8 ⁄ CXCL8 is present in high quantities in both the synovial tissue and synovial fluid of RA patients, and synovial tissue macrophages constitutively pro- is duce known to have angiogenic activity in the RA joint [31]. Strong also observed in primary cultures of articular chondro- cytes as well as in cartilage explants stimulated with IL-1b [32].

Fractalkine ⁄ CX3CL1, a chemoattractant for mono- cytes and lymphocytes, is significantly elevated in RA synovial fluid compared with synovial fluid from patients with OA or other forms of arthritis. The syno- vial fluid and peripheral blood of patients with RA contain a greater percentage of monocytes expressing fractalkine ⁄ CX3CL1 and CX3CR1 compared with T cells [43]. Recombinant human fractalkine ⁄ CX3CL1 significantly induces the migration of human dermal microvascular endothelial cells, suggesting that it may mediate angiogenesis in RA [44]. The secretion of frac- talkine ⁄ CX3CL1 from FLS obtained from RA patients is regulated mainly by TNF-a.

The role of chemokines in RA pathogenesis

Growth-related oncogene a (GROa) ⁄ CXCL1 (a ligand of CXCR2), a chemoattractant for neutrophils, similarly to IL-8 ⁄ CXCL8, is highly expressed in syno- vial fluid and synovial tissue in RA patients. Further- more, the production of GROa ⁄ CXCL1 by RA FLS and chondrocytes is significantly increased upon incu- bation with TNF-a or IL-1b [16,33,34]. Interleukin-17 also induces the expression of GROa ⁄ CXCL1 mRNA, as well as the expression of IL-8 ⁄ CXCL8 mRNA, which is dependent on p38 mitogen-activated protein kinase (MAPK) in RA FLS [35]. Growth-related onco- gene a ⁄ CXCL1 induces a dose-dependent decrease in the expression of interstitial collagens by rheumatoid synovial fibroblasts [36].

The chemokines listed above are implicated in RA pathogenesis via the recruitment and retention of leu- kocytes in the joints. In addition to functioning in cell trafficking, several chemokines have been shown to possess other biological abilities [45].

Interferon-c-inducible protein-10 (IP-10) ⁄ CXCL10 (a ligand of CXCR3) is also upregulated in RA synovial fluid and synovial tissue [9,37]. Immunolocalization analysis indicated that IP-10 ⁄ CXCL10 is associated mainly with infiltrating macrophage-like cells and fibroblast-like cells in the RA synovium, and the inter- action of activated leukocytes with FLS results in marked increases in the expression and secretion of IP-10 ⁄ CXCL10 [37]. Human chondrocytes also produce IP-10 ⁄ CXCL10 stimulated by the pro-inflammatory cytokines IL-1b or TNF-a [38].

Stromal

Monokine induced by interferon-c (Mig) ⁄ CXCL9, also a ligand of CXCR3, is highly expressed in RA synovial fluid and synovial tissue, particularly in macrophages [9]. The expression of Mig ⁄ CXCL9 by cultured FLS is stimulated by IFN-c [39]. cell-derived factor

that SDF-1 ⁄ CXCR4

(SDF)-1 ⁄ CXCL12, a ligand of CXCR4, is expressed in the RA synovium and is increased by CD40 stimulation [40]. Stromal cell-derived factor-1 ⁄ CXCL12 stimulates the migration of CD4+ memory T cells in the RA synovium and also inhibits activation-induced apoptosis of T cells, interactions play indicating important roles in CD4+ memory T-cell accumulation in the RA synovium [40].

Chemokines are able to stimulate FLS and chon- drocytes to release inflammatory mediators, including cytokines and matrix metalloproteinases (MMPs), leading to cartilage degradation. Stimulation of RA FLS with MCP-1 ⁄ CCL2, RANTES ⁄ CCL5 and SDF- 1 ⁄ CXCL12 results in the enhanced production of IL-6 and IL-8 ⁄ CXCL8 [46]. Monocyte chemoattractant IP-10 ⁄ CXCL10, protein-1 ⁄ CCL2, SDF-1 ⁄ CXCL12, RANTES ⁄ CCL5 and Mig ⁄ CXCL9 increase, in a dose-dependent and time-dependent manner, the gela- tinase and collagenase activities in the supernatants of cultured FLS [47]. Monocyte chemoattractant pro- tein-1 ⁄ CCL2 and RANTES ⁄ CCL5 stimulate MMP-3 production by chondrocytes and are also able to inhibit proteoglycan synthesis and to enhance proteo- glycan release from the chondrocytes [48,49]. RAN- TES ⁄ CCL5 induces the expression of inducible nitric oxide synthase, IL-6 and MMP-3 in chondrocytes [50]. The release of MMP-3 is also increased by stimulating chondrocytes with SDF-1 ⁄ CXCL12 [10]. The interaction of SDF-1 ⁄ CXCL12 with CXCR4-

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and

SDF-1 ⁄ CXCL12

these cells,

positive chondrocytes results in a specific increase in the release of MMP-3 [10]. Pathological concentra- tions of SDF-1 ⁄ CXCL12 induce the death of human chondrocytes and this is dependent on the p38 MAPK activity [51]. Lymphotactin ⁄ XCL1 stimulation of RA FLS results in a marked downregulation of MMP-2 production [52]. Thus, chemokines released by mononuclear cells and FLS, or by the chondro- cytes themselves, can induce an autocrine ⁄ paracrine stimulation of leading to extracellular matrix degradation.

fractalkine ⁄ MCP-1 ⁄ CCL2, CX3CL1, are also known to have angiogenic proper- ties [44,58,59]. Recently, associations between the chemokine gene polymorphisms and RA have been investigated. An allelic variant in the 3¢-untranslated region of the SDF-1 gene is associated with the annual rates of radiographic progression, but not with suscep- tibility to RA. However, the functional role of these variants has not been clearly established thus far [60]. A recent meta-analysis reported a significant, negative association of a 32-bp deletion in the CCR5 gene (CCR5D32), which results in a nonfunctional receptor, with susceptibility to RA, suggesting that CCR5D32 is protective against the development of RA [61]. The gene copy number variations of CCL3-like 1 (CCL3L1), a nonallelic isoform of CCL3 encoded by different genes and a potent ligand for CCR1 and CCR5, influenced susceptibility to RA, and genetic interaction between CCL3L1 dose and CCR5D32 was also found [62]. These results indicate that the genetic variations of chemokines and chemokine receptors are associated with RA susceptibility and severity.

for

Conclusion

inflammation,

several animal

Furthermore, chemokines have the ability to enhance leading to synovial hyperplasia. cell proliferation, Stimulation with MCP-1 ⁄ CCL2, SDF-1 ⁄ CXCL12, IP-10 ⁄ CXCL10, Mig ⁄ CXCL9 and MCP-4 ⁄ CCL13 enhances the proliferation of FLS [13,47]. Our group the proliferation of FLS by MCP- reported that 4 ⁄ CCL13 is dependent on activation of the extracellu- lar regulated kinase MAPK. The activation of MAPK is also important in regulating the RA FLS cytoskeletal structure and migration by fractalkine ⁄ CX3CL1 [53]. Fractalkine ⁄ CX3CL1 was expressed on FLS, and senescent CD28) T cells were positive for CX3CR1, the receptor fractalkine ⁄ CX3CL1. Fractalkine ⁄ CX3CL1 was expressed on FLS costimulated T-cell- activating signals and amplified the proliferation, IFN-c production and expulsion of cytoplasmic gran- ules [54]. In addition, fractalkine ⁄ CX3CL1 not only regulated T-cell function, but directly affected FLS pro- liferation, suggesting that T-cell ⁄ FLS interactions led to an autocrine growth-promoting loop enhancing the proliferative expansion of FLS [55].

Chemokines have an important role in the patho- genesis of RA by recruiting leukocytes and by control- ling other important processes, such as release of cell proliferation and mediators of studies and angiogenesis. To date, human studies have shown the biological efficacy of specific antagonism of ligands and receptors in RA [45,63]. Thus, chemokines are key molecules in the pathogenesis of RA, and chemokine targeting has significant promise as an anti-RA strategy.

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