Chemokines and leukocyte trafficking in rheumatoid arthritis

doi:10.1016/j.pathophys.2005.11.001

Pathophysiology

Volume 13, Issue 1, 21 February 2006, Pages 1-14

https://doi.org/10.1016/j.pathophys.2005.11.001 Get rights and content

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.

Section snippets

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)

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 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

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

Therapeutic considerations

Inhibitors to adhesion molecules have had some success in animal models of inflammatory arthritis. A P-selectin glycoprotein ligand (rPSGL-1Ig) fusion protein was able to ameliorate established CIA in mice, partially through decreased production of TNF-α [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

Conclusions

Although anti-TNF-α 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-α 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.

References (139)

T.A. Springer
Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm
Cell
(1994)
S.D. Rosen et al.
The selectins and their ligands
Curr. Opin. Cell Biol.
(1994)
R.W. McMurray
Adhesion molecules in autoimmune disease
Semin. Arthritis Rheum.
(1996)
K. Ley et al.
Lectin-like cell adhesion molecule 1 mediates leukocyte rolling in mesenteric venules in vivo
Blood
(1991)
R. Hallmann et al.
The peripheral lymph node homing receptor, LECAM-1, is involved in CD18-independent adhesion of human neutrophils to endothelium
Biochem. Biophys. Res. Commun.
(1991)
M.L. Arbones et al.
Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice
Immunity
(1994)
G.M. Venturi et al.
Leukocyte migration is regulated by L-selectin endoproteolytic release
Immunity
(2003)
D. Kohda et al.
Solution structure of the link module: a hyaluronan-binding domain involved in extracellular matrix stability and cell migration
Cell
(1996)
T. Imai et al.
Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion
Cell
(1997)
A.M. Fong et al.
Ultrastructure and function of the fractalkine mucin domain in CX(3)C chemokine domain presentation
J. Biol. Chem.
(2000)

A.M. Fong et al.

CX3CR1 tyrosine sulfation enhances fractalkine-induced cell adhesion

J. Biol. Chem.

(2002)

S.D. Marlin et al.

Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1)

Cell

(1987)

C. Laudanna et al.

Elevation of intracellular cAMP inhibits RhoA activation and integrin-dependent leukocyte adhesion induced by chemoattractants

J. Biol. Chem.

(1997)

L.A. Robinson et al.

The chemokine CX3CL1 regulates NK cell activity in vivo

Cell Immunol.

(2003)

J. Guo et al.

Chemoattraction, adhesion and activation of natural killer cells are involved in the antitumor immune response induced by fractalkine/CX3CL1

Immunol. Lett.

(2003)

R. Wilkinson et al.

Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) acts as a regulator of B-cell development, B-cell antigen receptor (BCR)-mediated activation, and autoimmune disease

Blood

(2002)

Z. Szekanecz et al.

Chemokines and chemokine receptors in rheumatoid arthritis

Semin. Immunol.

(2003)

H. Arai et al.

Differential regulation of G-protein-mediated signaling by chemokine receptors

J. Biol. Chem.

(1996)

Y. Kuang et al.

Selective G protein coupling by C-C chemokine receptors

J. Biol. Chem.

(1996)

M.J. Lohse et al.

Receptor-specific desensitization with purified proteins. Kinase dependence and receptor specificity of beta-arrestin and arrestin in the beta 2-adrenergic receptor and rhodopsin systems

J. Biol. Chem.

(1992)

S. Ahn et al.

Reciprocal regulation of angiotensin receptor-activated extracellular signal-regulated kinases by beta-arrestins 1 and 2

J. Biol. Chem.

(2004)

A. Tohgo et al.

The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation

J. Biol. Chem.

(2003)

L.M. Ebert et al.

Chemokine-mediated control of T cell traffic in lymphoid and peripheral tissues

Mol. Immunol.

(2005)

F. Sallusto et al.

Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses

Immunol. Today

(1998)

R. Forster et al.

A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen

Cell

(1996)

R. Forster et al.

CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs

Cell

(1999)

S. Hosaka et al.

Soluble forms of P-selectin and intercellular adhesion molecule-3 in synovial fluids

Clin. Immunol. Immunopathol.

(1996)

A.C. Issekutz et al.

A major portion of polymorphonuclear leukocyte and T lymphocyte migration to arthritic joints in the rat is via LFA-1/MAC-1-independent mechanisms

Clin. Immunol. Immunopathol.

(1993)

D.D. Patel et al.

CXCR3 and CCR5 ligands in rheumatoid arthritis synovium

Clin. Immunol.

(2001)

A.E. Koch et al.

Macrophage inflammatory protein-1 beta: a C-C chemokine in osteoarthritis

Clin. Immunol. Immunopathol.

(1995)

M.V. Volin et al.

RANTES expression and contribution to monocyte chemotaxis in arthritis

Clin. Immunol. Immunopathol.

(1998)

C. Laudanna et al.

Role of Rho in chemoattractant-activated leukocyte adhesion through integrins

Science

(1996)

A.M. Fong et al.

Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow

J. Exp. Med.

(1998)

D.D. Patel et al.

Leukocyte homing to synovium

Curr. Dir. Autoimmun.

(2001)

B.F. Haynes et al.

Measurement of an adhesion molecule as an indicator of inflammatory disease activity. Up-regulation of the receptor for hyaluronate (CD44) in rheumatoid arthritis

Arthritis Rheum.

(1991)

K. Ley et al.

Leukocyte interactions with vascular endothelium. New insights into selectin-mediated attachment and rolling

J. Immunol.

(1995)

T.F. Tedder et al.

The selectins: vascular adhesion molecules

FASEB J.

(1995)

C.A. Janeway, P. Travers, M. Walport, M.J. Schlomchik, Immunobiology; the immune system in health and disease, 6th ed.,...

M.P. Bevilacqua et al.

Identification of an inducible endothelial-leukocyte adhesion molecule

Proc. Natl. Acad. Sci. U.S.A.

(1987)

S.S. To et al.

Regulation of adhesion molecule expression by human synovial microvascular endothelial cells in vitro

Arthritis Rheum.

(1996)

J. Kriegsmann et al.

Expression of E-selectin messenger RNA and protein in rheumatoid arthritis

Arthritis Rheum.

(1995)

P.P. Tak et al.

Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis

Arthritis Rheum.

(1996)

W.M. Gallatin et al.

A cell-surface molecule involved in organ-specific homing of lymphocytes

Nature

(1983)

T.F. Tedder et al.

Human antigen-specific memory T cells express the homing receptor (LAM-1) necessary for lymphocyte recirculation

Eur. J. Immunol.

(1990)

U.H. Von Andrian et al.

L-selectin function is required for beta 2-integrin-mediated neutrophil adhesion at physiological shear rates in vivo

Am. J. Physiol.

(1992)

O. Spertini et al.

Leukocyte adhesion molecule-1 (LAM-1, L-selectin) interacts with an inducible endothelial cell ligand to support leukocyte adhesion

J. Immunol.

(1991)

M.L. Tang et al.

Intrinsic differences in L-selectin expression levels affect T and B lymphocyte subset-specific recirculation pathways

J. Immunol.

(1998)

J.R. Allport et al.

L-selectin shedding does not regulate human neutrophil attachment, rolling, or transmigration across human vascular endothelium in vitro

J. Immunol.

(1997)

E. Galkina et al.

L-selectin shedding does not regulate constitutive T cell trafficking but controls the migration pathways of antigen-activated T lymphocytes

J. Exp. Med.

(2003)

H.C. DeGrendele et al.

CD44 and its ligand hyaluronate mediate rolling under physiologic flow: a novel lymphocyte-endothelial cell primary adhesion pathway

J. Exp. Med.

(1996)

Cited by (55)

Role of CCL2/CCR2 axis in the immunopathogenesis of rheumatoid arthritis: Latest evidence and therapeutic approaches
2021, Life Sciences
Citation Excerpt :
Like other rheumatic diseases, RA is an AD and the immune system, which in normal condition protects the body against infections and diseases, attacks the joint tissue for unknown reasons [12]. Thus, leukocytes, which are important players in the immune system, migrate to the synovium and cause inflammation, resulting in joint pain and swelling along with bone and cartilage destruction [13]. During the mentioned inflammatory state, the synovium tissue, which is normally thin, gradually thickens and causes the joints to swell [14].
Evidence suggests that uncontrolled immune system responses and their components play a significant role in developing rheumatoid arthritis (RA), which is considered an autoimmune disease (AD). Among immune system mediators, cytokines and chemokines are involved in numerous physiological and pathological processes. CCL2 or monocyte chemoattractant protein-1 (MCP-1) is known as a CC chemokine that can induce the locomotion and recruitment of monocytes and macrophages to the site of injury. When CCL2 binds to its receptors, the most important of which is CCR2, various signaling pathways are triggered, eventually leading to various immunological events such as inflammation. This chemokine also participates in several events involved in RA pathogenesis, such as osteoclastogenesis, migration of effector T cells to the RA synovium tissue, and angiogenesis. In this review article, the role of the CCL2/CCR2 axis in RA pathogenesis and the immunotherapy opportunities based on CCL2/CCR2 axis targeting has been discussed based on existing investigations.
The joint synovium: A critical determinant of articular cartilage fate in inflammatory joint diseases
2017, Seminars in Cell and Developmental Biology
Citation Excerpt :
During the initial phase of RA, the chemokines, cytokines and growth factors produced by the transformed FLS affect not only chondrocytes and macrophage-like synoviocytes, but also stimulate the neighboring EC to express a variety of leukocyte adhesion molecules, including E-selectin, P-selectin, intracellular adhesion molecule 1 and vascular cell adhesion molecule 1. By interacting with specific leukocyte receptors (e.g., integrins, L-selectin and Sialyl Lewis X), these adhesion molecules cause the rolling, firm adhesion and transmigration of leukocytes from the blood circulation into the synovial cavity [57,58]. Upon infiltration, leukocytes in turn secrete growth factors, cytokines and metalloproteinases that aggravate the processes of cartilage damage and degradation.
The synovium constitutes the envelope of articular joints and is a critical provider of synovial fluid components and articular cartilage nutrients. Its inflammation is a predominant feature and cause of joint degeneration in diseases as diverse as rheumatoid, psoriatic, juvenile and idiopathic arthritis, and lupus, gout and lyme disease. These inflammatory joint diseases (IJDs) are due to a wide variety of genetic, epigenetic and environmental factors that trigger, promote, and perpetuate joint destabilization. In spite of this variety of causes, IJDs share main pathological features, namely inflammation of the joint synovium (synovitis) and progressive degeneration of articular cartilage. In addition to being a driving force behind the destruction of articular cartilage in IJD, synovitis is also increasingly being recognized as a significant contributor of articular cartilage degeneration in osteoarthritis, a disease primarily due to aging- or trauma-related wear and tear of cartilage surfaces. In view of this important role of the synovium in determining the fate of articular cartilage, this review focuses on its underlying mechanisms in the pathology of IJD. We address the roles of synovial fibroblasts, macrophages and endothelial cells in the maintenance of joint health and in the destruction of articular cartilage integrity during IJD. Molecular mechanisms that have been recently shown to govern the pathological activities of the resident synovial cells are highlighted. Finally, advantages and disadvantages of targeting these new molecular mechanisms for preventing cartilage degeneration due to chronic inflammation are also discussed.
Cellular gene expression induced by parasite antigens and allergens in neonates from parasite-infected mothers
2016, Molecular Immunology
Citation Excerpt :
Parasite antigens and allergens induced the gene expression of several CC as well as CXC chemokines which play an essential role in leukocyte trafficking, cell tissue infiltration and inflammation (Oliveira and Lukacs, 2003). They are important mediators between innate and adaptive immunity by regulating T cell differentiation, apoptosis, angiogenesis and metastatic processes, are functionally involved in regulation of Th1 or Th2 polarization, and monocyte and macrophage activation (Luther and Cyster, 2001; Tarrant and Patel, 2006; Esche et al., 2005). The pronounced expression in Para-NEG of CCL2/MCP1, CCL5/RANTES, CCL7/MCP3, CCL8/MCP2, CCL13/MCP4 genes corresponded with the expression of their receptors CCR1 and CCR2.
Prenatal exposure to parasite antigens or allergens will influence the profile and strength of postnatal immune responses, such contact may tolerize and increase susceptibility to future infections or sensitize to environmental allergens. Exposure in utero to parasite antigens will distinctly alter cellular gene expression in newborns. Gene microarrays were applied to study gene expression in umbilical cord blood cell (UCBC) from parasite-exposed (Para-POS) and non-exposed (Para-NEG) neonates. UCBC were activated with antigens of helminth (Onchocerca volvulus), amoeba (Entamoeba histolytica) or allergens of mite (Dermatophagoides farinae). When UCBC from Para-POS and Para-NEG newborns were exposed to helminth antigens or allergens consistent differences occurred in the expression of genes encoding for MHC class I and II alleles, signal transducers of activation and transcription (STATs), cytokines, chemokines, immunoglobulin heavy and light chains, and molecules associated with immune regulation (SOCS, TLR, TGF), inflammation (TNF, CCR) and apoptosis (CASP). Expression of genes associated with innate immune responses were enhanced in Para-NEG, while in Para-POS, the expression of MHC class II and STAT genes was reduced. Within functional gene networks for cellular growth, proliferation and immune responses, Para-NEG neonates presented with significantly higher expression values than Para-POS. In Para-NEG newborns, the gene cluster and pathway analyses suggested that gene expression profiles may predispose for the development of immunological, hematological and dermatological disorders upon postnatal helminth parasite infection or allergen exposure. Thus, prenatal parasite contact will sensitize without generating aberrant inflammatory immune responses, and increased pro-inflammatory but decreased regulatory gene expression profiles will be present in those neonates lacking prenatal parasite antigen encounter.
G-protein signaling modulator-3, a gene linked to autoimmune diseases, regulates monocyte function and its deficiency protects from inflammatory arthritis
2013, Molecular Immunology
Citation Excerpt :
Ly6C-enriched/CD11b+ splenocytes from Gpsm3−/− mice had significantly reduced chemotaxis toward CCL2/MCP-1, CX3CL1/FKN, and chemerin, although no statistical differences were observed for CCL3/MIP-1α or CCL5/RANTES (Fig. 3C). Monocytes are critical to autoimmune arthritis disease pathogenesis through their roles in antigen presentation and production of pro-inflammatory cytokines (Ambarus et al., 2012; Rong et al., 2012); in particular, chemotaxis of circulating monocytes toward the inflamed joint, and their subsequent differentiation into proinflammatory macrophages, is critical to the development and exacerbation of RA (Tarrant and Patel, 2006). Our results support a key role of GPSM3 in monocyte function and in disease pathogenesis in an acute inflammatory arthritis disease model – a finding that, in turn, strengthens the association of human GPSM3 polymorphisms in autoimmune diseases including RA and AS (Sirota et al., 2009; Corona et al., 2010).
Polymorphism at the GPSM3 gene locus is inversely associated with four systemic autoimmune diseases, including rheumatoid arthritis and ankylosing spondylitis. G-protein signaling modulator-3 (GPSM3) expression is most pronounced in myeloid cells, in which it targets heterotrimeric G-protein Gαi subunits of chemokine receptors, critical to immune function. To begin to explore the regulatory role of GPSM3 in monocytes, human THP-1 and primary mouse myeloid cells were cultured under stimulus conditions; GPSM3 was found by immunoblotting to be expressed at highest levels in the mature monocyte. To evaluate the effects of GPSM3 deficiency on a myeloid-dependent autoimmune disease, collagen antibody-induced arthritis (CAIA) was induced in Gpsm3−/− and control mice, which were then analyzed for clinical score, paw swelling, intra-articular proinflammatory markers, and histopathology. Mice lacking GPSM3 were protected from CAIA, and expression of monocyte-representative pro-inflammatory chemokine receptors and cytokines in paws of Gpsm3−/− mice were decreased. Flow cytometry, apoptosis, and transwell chemotaxis experiments were conducted to further characterize the effect of GPSM3 deficiency on survival and chemokine responsiveness of monocytes. GPSM3-deficient myeloid cells had reduced migration ex vivo to CCL2, CX3CL1, and chemerin and enhanced apoptosis in vitro. Our results suggest that GPSM3 is an important regulator of monocyte function involving mechanisms of differentiation, survival, and chemotaxis, and deficiency in GPSM3 expression is protective in acute inflammatory arthritis.
Dimension-agnostic and granularity-based spatially variable gene identification using BSP
2023, Nature Communications
Dimension-agnostic and granularity-based spatially variable gene identification
2023, Research Square

View all citing articles on Scopus

: This paper was part of the Rheumatoid Special Issue, See Pathophysiology 12/3.

View full text

Chemokines and leukocyte trafficking in rheumatoid arthritis

Abstract

Section snippets

Leukocyte migration

Chemokines and chemokine receptors

Regulation of leukocyte trafficking to inflamed synovium

Therapeutic considerations

Conclusions

Cell

Curr. Opin. Cell Biol.

Semin. Arthritis Rheum.

Blood

Biochem. Biophys. Res. Commun.

Immunity

Immunity

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

Cell Immunol.

Immunol. Lett.

Blood

Semin. Immunol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Immunol.

Immunol. Today

Cell

Cell

Clin. Immunol. Immunopathol.

Clin. Immunol. Immunopathol.

Clin. Immunol.

Clin. Immunol. Immunopathol.

Clin. Immunol. Immunopathol.

Role of Rho in chemoattractant-activated leukocyte adhesion through integrins

Science

Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow

J. Exp. Med.

Leukocyte homing to synovium

Curr. Dir. Autoimmun.

Measurement of an adhesion molecule as an indicator of inflammatory disease activity. Up-regulation of the receptor for hyaluronate (CD44) in rheumatoid arthritis

Arthritis Rheum.

Leukocyte interactions with vascular endothelium. New insights into selectin-mediated attachment and rolling

J. Immunol.

The selectins: vascular adhesion molecules

FASEB J.

Identification of an inducible endothelial-leukocyte adhesion molecule

Proc. Natl. Acad. Sci. U.S.A.

Regulation of adhesion molecule expression by human synovial microvascular endothelial cells in vitro

Arthritis Rheum.

Expression of E-selectin messenger RNA and protein in rheumatoid arthritis

Arthritis Rheum.

Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis

Arthritis Rheum.

A cell-surface molecule involved in organ-specific homing of lymphocytes

Nature

Human antigen-specific memory T cells express the homing receptor (LAM-1) necessary for lymphocyte recirculation

Eur. J. Immunol.

L-selectin function is required for beta 2-integrin-mediated neutrophil adhesion at physiological shear rates in vivo

Am. J. Physiol.

Leukocyte adhesion molecule-1 (LAM-1, L-selectin) interacts with an inducible endothelial cell ligand to support leukocyte adhesion

J. Immunol.

Intrinsic differences in L-selectin expression levels affect T and B lymphocyte subset-specific recirculation pathways

J. Immunol.

L-selectin shedding does not regulate human neutrophil attachment, rolling, or transmigration across human vascular endothelium in vitro

J. Immunol.

L-selectin shedding does not regulate constitutive T cell trafficking but controls the migration pathways of antigen-activated T lymphocytes

J. Exp. Med.

CD44 and its ligand hyaluronate mediate rolling under physiologic flow: a novel lymphocyte-endothelial cell primary adhesion pathway

J. Exp. Med.