Te Many Role Od Chemokines and Chemokine Receptors in Inflammation

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review article

Th e n e w e n g l a n d j o u r n a l o f m ed i c i n e

n engl j med 354;6 www.nejm.org february 9, 2006610

MECHANISMS OF DISEASE

The Many Roles of Chemokines andChemokine Receptors in Inflammation

Israel F. Charo, M.D., Ph.D., and Richard M. Ransohoff, M.D.

From the Gladstone Institute of Cardio-vascular Disease and the CardiovascularResearch Institute, Department of Medi-cine, University of California, San Francis-co both in San Francisco (I.F.C.); andthe Neuroinflammation Research Center,Department of Neurosciences, Lerner Re-search Institute, the Mellen Center for MSTreatment and Research, and the Cleve-

land Clinic Lerner College of Medicine,Cleveland Clinic Foundation, Cleveland(R.M.R.). Address reprint requests to Dr.Charo at the Gladstone Institute of Car-diovascular Disease, 1650 Owens St.,San Francisco, CA 94158, or at [email protected]; or to Dr. Ransohoffat the Department of Neurosciences,NC30, the Cleveland Clinic, 9500 EuclidAve., Cleveland, OH 44195, or at [email protected].

N Engl J Med 2006;354:610-21.Copyright 2006 Massachusetts Medical Society.

Chemokines (chemotactic cytokines) are small heparin-bindingproteins that direct the movement of circulating leukocytes to sites of in-

flammation or injury. During the eight years since chemokines and chemo-kine receptors were last reviewed in the Journal,1 a vast expansion in the understand-

ing of chemokine biology has occurred. Originally studied because of their role ininf lammation, chemokines and their receptors are now known to play a crucialpart in directing the movement of mononuclear cells throughout the body, engender-

ing the adaptive immune response and contributing to the pathogenesis of a varietyof diseases. Chemokine receptors are some of the most tractable drug targets in the

huge battery of molecules that regulate inf lammation and immunity. For this rea-son, clinical trials involving chemokine-receptor antagonists for the treatment of

inf lammatory conditions have recently begun. In this review, we survey the prop-erties of chemokines and their receptors and highlight the roles of these chemo-attractants in selected clinical disorders.

The approximately 50 human chemokines segregate into four families on thebasis of differences in structure and function (Tables 1 and 2).1-5 A systematic no-

menclature has been adopted in the past several years.6,7 The largest family con-sists of CC chemokines, so named because the first two of the four cysteine residues

in these molecules are adjacent to each other. CC chemokines attract mononu-clear cells to sites of chronic inf lammation. The most thoroughly characterized

CC chemokine is monocyte chemoattractant protein 1 (MCP-1), termed chemo-kine ligand CCL2 in the systematic nomenclature. It is a potent agonist for mono-cytes, dendritic cells, memory T cells, and basophils. Other CC chemokines in-

clude macrophage inflammatory protein (MIP)-1 (CCL3), MIP-1 (CCL4), andRANTES (CCL5). It is likely that dimers or even tetramers are the active form of

many CC chemokines.8

A second family of chemokines consists of CXC chemokines, which have asingle amino acid residue interposed between the first two canonical cysteines.

Some CXC chemokines, of which interleukin-8 (CXCL8) is the prototype, attractpolymorphonuclear leukocytes to sites of acute inflammation. CXCL8 also acti-

vates monocytes9,10 and may direct the recruitment of these cells to vascular lesions.The third family is the CX3C family, of which fractalkine (CX3CL1)11,12 is the only

member. The chemokine domain of CX3CL1 is fused to a mucin-like stalk andtransmembrane and cytoplasmic regions, thereby forming a cell-adhesion receptorcapable of arresting cells under physiologic flow conditions.13,14 An enzyme,

tumor necrosis factor (TNF)-converting enzyme, can cleave CX3CL1 from thecell membrane,15,16 freeing the cytokine to function as a soluble chemoattractant.

CXCL16, the other chemokine with a chemokine domain linked to a mucin stalk,also mediates cell adhesion and can be released as a soluble chemoattractant.17,18

CXCL16, present on macrophages and dendritic cells, mediates interactions between


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Mechanisms of disease

n engl j med 354;6 www.nejm.org february 9, 2006 611

antigen-presenting cells and T cells. CXCL16 also

has scavenger-receptor activity for oxidized lipidscontaining phosphatidylserine and may partici-pate in atherogenesis.18,19 Lymphotactin (XCL1),the sole member of the fourth family, has a single

cysteine residue.20

Chemokines affect cells by activating surface

receptors that are seven-transmembranedomainG-proteincoupled receptors; leukocyte responses

to particular chemokines are determined by theircomplement of chemokine receptors. The bindingof the chemokine to the receptor activates signal-

ing cascades that culminate in the rearrange-ment, change of shape, and cell movement of

actin. Unlike other chemokine receptors, CXCR4is expressed in many tissues, including those of

the central nervous system. In mice, the targeteddeletion of CXCR4 or its ligand, CXCL12, causesperinatal death, indicating that this ligand and

its receptor have a vital developmental func-tion.21,22

Chemokines, ChemokineReceptors, and Innate Immunity

The ELR+ CXC Chemokines

A subfamily of CXC chemokines that have a char-

acteristic glutamateleucinearginine (ELR) motifnear the N terminal of the molecule are chemo-

attractants of neutrophils and contribute to woundrepair. CXC chemokines (designated ELR+), suchas CXCL8, bind the neutrophil receptors CXCR1

and CXCR2 to each other.23 ELR+ CXC chemo-kines are encoded in a multigene array on chromo-

some 4. A key function of ELR+ CXC chemokinesis to attract neutrophils to sites of inflammation

and induce granule exocytosis and the respiratoryburst. Mediators of inflammation, including in-terleukin-1 and TNF-, or bacterial products such

as lipopolysaccharide elicit the production of ELR+CXC chemokines. It is clear that ELR+ CXC chemo-

kines orchestrate the early phases of wound heal-ing, but why mammals have seven similar ELR+

Table 1. CC Family of Chemokines and Chemokine Receptors.*

Receptor Chemokine Ligands Cell Types Disease Connection

CCR1 CCL3 (MIP-1), CCL5 (RANTES), CCL7 (MCP-3),CCL14 (HCC1)

T cells, monocytes, eosinophils,basophils

Rheumatoid arthritis, multiple scle-rosis

CCR2 CCL2 (MCP-1), CCL8 (MCP-2), CCL7 (MCP-3),CCL13 (MCP-4), CCL16 (HCC4)

Monocytes, dendritic cells (imma-ture), memory T cells

Atherosclerosis, rheumatoid arthritis,multiple sclerosis, resistance tointracellular pathogens, type 2diabetes mellitus

CCR3 CCL11 (eotaxin), CCL13 (eotaxin-2), CCL7 (MCP-3),CCL5 (RANTES), CCL8 (MCP-2), CCL13 (MCP-4)

Eosinophils, basophils, mast cells,Th2, platelets

Allergic asthma and rhinitis

CCR4 CCL17 (TARC), CCL22 (MDC) T cells (Th2), dendritic cells (mature),basophils, macrophages, platelets

Parasitic infection, graft rejection,T-cell homing to skin

CCR5 CCL3 (MIP-1), CCL4 (MIP-1), CCL5 (RANTES),CCL11 (eotaxin), CCL14 (HCC1), CCL16 (HCC4)

T cells, monocytes HIV-1 coreceptor (T-tropic strains),transplant rejection

CCR6 CCL20 (MIP-3, LARC) T cells (T regulatory and memory),B cells, dendritic cells

Mucosal humoral immunity, allergicasthma, intestinal T-cell homing

CCR7 CCL19 (ELC), CCL21 (SLC) T cells, dendritic cells (mature) Transport of T cells and dendriticcells to lymph node, antigen pre-sentation, and cellular immunity

CCR8 CCL1 (I309) T cells (Th2), monocytes, dendriticcells Dendritic-cell migration to lymphnode, type 2 cellular immunity,granuloma formation

CCR9 CCL25 (TECK) T cells, IgA+ plasma cells Homing of T cells and IgA+ plasmacells to the intestine, inflammatorybowel disease

CCR10 CCL27 (CTACK), CCL28 (MEC) T cells T-cell homing to intestine and skin

* MIP denotes macrophage inflammatory protein, MCP monocyte chemoattractant protein, HCC hemofiltrate chemokine, Th2 type 2 helperT cells, TARC thymus and activation-regulated chemokine, MDC macrophage-derived chemokine, LARC liver and activation-regulatedchemokine, ELC EpsteinBarr I1-ligand chemokine, SLC secondary lymphoid-tissue chemokine, TECK thymus-expressed chemokine, CTACKcutaneous T-cellattracting chemokine, and MEC mammary-enriched chemokine.


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CXC chemokines remains enigmatic especiallysince unique functional roles have not been found

for most of them.24,25

Both ELR and ELR+ CXC chemokines havebeen linked to angiogenesis.26,27 Vascularization

of the gastrointestinal tract is defective in micelacking either CXCR4 or its ligand, CXCL12.28

CXCR2 appears on endothelial cells during wound

healing,29 and wound epithelialization and neo-vascularization are considerably delayed in CXCR2-knockout mice.30 The medical implications ofthese findings are wide ranging. A blockade of

CXCR1 or CXCR2 could inhibit excessive infiltra-tion or activation of neutrophils during acute

inflammatory processes.23 Modulation of theangiogenic action of ELR or ELR+ CXC chemo-

kines holds promise for cancer treatment.27

Different chemokine families may interact

during the formation of blood vessels. Severalchemokines without the ELR motif, includingCXCL4 and the ligands for CXCR3, antagonize

angiogenesis. It has been shown in model sys-tems that chemokine-mediated antiangiogenic

properties can antagonize cardinal angiogenicfactors such as endothelial growth factor and

basic fibroblast growth factor.27 Early productionof ELR+ CXC chemokines might promote theformation of granulation tissue and the protec-

tion of wound sites by attracting neutrophils andby inducing fibroblast differentiation and angio-

genesis, whereas certain ELR CXC chemokines,produced later, could restrain angiogenesis.

Monocyte Chemoattractant Proteins

The monocyte chemoattractant proteins recruit

monocytes to sites of trauma, bacterial and myco-

bacterial infection, toxin exposure, and ischemia.These proteins consist of a group of related pep-tides CCL2, CCL7, CCL8, and CCL13 en-coded on chromosome 17.31,32 As with the seven

ELR+ CXC chemokines, distinct functional attri-butes of the four monocyte chemoattractant pro-

teins have not been identified. CCR2 is the onlyknown receptor for CCL2 and CCL13,33,34 where-

as CCL8 binds to both CCR2 and CCR5 and CCL7binds to CCR1, CCR2, and CCR3. Studies of

knockout mice indicate that CCL2 has a nonre-dundant role in regulating the infiltration ofmonocytes during inflammation.31 Moreover,

under a broad range of stimuli, CCL2- and CCR2-knockout mice exhibit deficient monocyte recruit-

ment in virtually every tissue.34

Because monocyte chemoattractant proteins

can attract basophils and eosinophils and inducedegranulation of these cells, they probably par-ticipate in allergic reactions. Moreover, mice that

Table 2. CXC, CX3C, and XC Families of Chemokines and Chemokine Receptors.*

Receptor Chemokine Ligands Cell Types Disease Connection

CXCR1 CXCL8 (interleukin-8), CXCL6 (GCP2) Neutrophils, monocytes Inflammatory lung disease, COPD

CXCR2 CXCL8, CXCL1 (GRO), CXCL2 (GRO), CXCL3(GRO), CXCL5 (ENA-78), CXCL6

Neutrophils, monocytes, micro-vascular endothelial cells

Inflammatory lung disease, COPD,angiogenic for tumor growth

CXCR3-A CXCL9 (MIG), CXCL10 (IP-10), CXCL11 (I-TAC) Type 1 helper cells, mast cells,mesangial cells

Inflammatory skin disease, multiplesclerosis, transplant rejection

CXCR3-B CXCL4 (PF4), CXCL9 (MIG), CXCL10 (IP-10),CXCL11 (I-TAC)

Microvascular endothelial cells,neoplastic cells

Angiostatic for tumor growth

CXCR4 CXCL12 (SDF-1) Widely expressed HIV-1 coreceptor (T-celltropic),tumor metastases, hematopoiesis

CXCR5 CXCL13 (BCA-1) B cells, follicular helper T cells Formation of B-cell follicles

CXCR6 CXCL16 (SR-PSOX) CD8+ T cells, natural killer cells,and memory CD4+ T cells

Inflammatory liver disease, atheroscle-rosis (CXCL16)

CX3CR1 CX3CL1 (fractalkine) Macrophages, endothelial cells,

smooth-muscle cellsAtherosclerosis

XCR1 XCL1 (lymphotactin), XCL2 T cells, natural killer cells Rheumatoid arthritis, IgA nephropathy,tumor response

* GCP denotes granulocyte chemotactic protein, COPD chronic obstructive pulmonary disease, GRO growth-regulated oncogene, ENA epithe-lial-cellderived neutrophil-activating peptide, MIG monokine induced by interferon-, IP-10 interferon-inducible protein 10, I-TAC interfer-on-inducible T-cell alpha chemoattractant, PF platelet factor, SDF stromal-cellderived factor, HIV human immunodeficiency virus, BCA-1B-cell chemoattractant 1, and SR-PSOX scavenger receptor for phosphatidylserine-containing oxidized lipids.


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have a deficiency of CCL2 have defects in the

production by antigen-primed lymphocytes ofthe type 2 helper cytokines that are involved in

the production of antibodies.35 Mice lacking thereceptor for CCL2 (CCR2) also have a profound

defect in the production of interferon-, a cytokine

that has an important role in inflammation.34

The production of monocyte chemoattractant

proteins and of the ELR+ CXC chemokines isintegral to innate immune responses. In these

responses, chemokines are secreted downstreamof the cellular recognition of pathogen-associated

molecules and the first wave of production ofinf lammatory cytokines, such as interleukin-1.Chemokines therefore couple the detection of

pathogens with the infiltration of tissues by neu-trophils and monocytes.

CCR7

CCR7 and its ligands link innate and adaptiveimmunity through their effects on interactionsbetween T cells and dendritic cells. During in-

nate immune responses, phagocytes and solublefactors rather nonspecifically eliminate or neu-

tralize pathogens. By contrast, the adaptive im-mune responses generated by B cells and T cells

have specificity and memory. Adaptive immunitybegins in lymphoid organs, where mature den-dritic cells or macrophages present immunogen-

ic peptides to naive or memory T cells (Fig. 1).This encounter is governed with remarkable pre-

cision by two chemokines, CCL19 and CCL21, and

their receptor, CCR7.36-38Once immature dendriticcells ingest antigen and become able to presentantigen to T cells, they increase their display ofCCR7.24 These CCR7+ dendritic cells enter lymph

nodes through the afferent lymph or the blood-stream, using vessel-bound CCL19 and CCL21 to

sense their destination. Naive or memory T cellsenter through high endothelial venules, using the

same receptors and cues. Once inside the lymphnode, CCR7+ dendritic cells and T cells follow

gradients of CCL19 and CCL21 in T-cell zones tofind one another. Given the low likelihood thatany individual dendritic cell will present the right

immunogenic peptide to a part icular T cell, thisprocess must be repeated continuously and with

high efficiency to increase the probability thatclones of antigen-specific T cells will be activated.2

Mice lacking CCR7 (through targeted genedeletion) or that have insufficient CCL19 or CCL21(through naturally occurring mutation) have struc-

turally disorganized lymph-node T-cell zones and

are deficient in T-celldependent immunity.39Another receptorligand pair, CXCR5 and CXCL13,

establish and coordinate the B-cell zones of lymphnodes.39,40 After antigen binding, B cells up-regu-

late CCR7 and move to the boundaries between

B-cell and T-cell zones to interact with helperT cells.41These insights have medical importance,

because the understanding of lymph-node func-tion is relevant to a variety of issues, including

the transport of human immunodeficiency virus(HIV) from mucosal surfaces to lymph nodes,

the enhancement of vaccines and immunother-apy, and the suppression of transplant rejectionand autoimmune disorders.

Movement of Lymphocytes toSkin and Gut

After an immune response subsides, CCR7+ mem-ory T cells continuously circulate through tissuesand lymph nodes by way of the bloodstream.

Many of these long-lived cells are specialized fordefending the skin or gastrointestinal tract against

pathogens, and they are directed to these sites byspecific homing signatures.42,43 For skin, the sig-

nature on the leukocyte is the CCR4cutaneouslymphocyte antigen 1 (CLA-1) pair, and for thegut, the signature on the leukocyte is CCR9

4

7

integrin. Binding partners for these moleculesare in the target tissue. The signatures are im-

printed on lymphocytes in draining lymph nodes,

in which antigen-presenting cells direct lympho-cytes to return to the organs in which they firstencountered antigen.44 Each major organ systemprobably has a unique area code that consists

of lymphocyte surface molecules and counter re-ceptors on endothelial beds.2 Indeed, initial indi-

cators of distinct leukocyte-homing determinantsfor the lungs, joints, and the brain have been

found, but much work remains to be done, includ-ing the identification of chemokine receptors on

the cells that home to these various organs.44

Coreceptors for HIV-1

To enter target cells, HIV type 1 (HIV-1) requires

two distinct recognition elements: CD4 and ei-ther CXCR4 (for T-celltropic strains) or CCR5

(for macrophage-tropic strains). The targetingof T cells and monocytes allows HIV-1 access tosanctuary sites throughout the body and also


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cripples the CD4+ T cells that orchestrate antivi-ral immunity.5,45,46 Compelling genetic evidenceof the central role of CCR5 in the pathogenesis of

HIV-1 came from the identification of multiplyexposed but uninfected persons, who proved to

be homozygous for a nonfunctional variant ofCCR5. Drugs that target these chemokine recep-

tors for HIV disease are currently in advanced-stage clinical trials.

I n flam m at ory Di seas es

Chemokines have been implicated in a wide rangeof diseases with prominent inflammatory compo-

nents. For example, elevated levels of CC chemo-kines, particularly CCL2, CCL3, and CCL5, in the

joints of patients with rheumatoid arthritis co-incide with the recruitment of monocytes and

T cells into synovial tissues. Inflammation is also

Figure 1. Movement of the Immune Cell through the Lymph Node.

Naive T cells enter the lymph node through high endothelial venules, which express the chemokine CCL21 (secondary lymphoid-tissue

chemokine, or SLC). Antigen-presenting cells, dendritic cells, and macrophages enter the lymph node through afferent lymphatics. Ma-

ture dendritic cells express CCR7, and macrophages express CCR2. T cells and dendritic cells together localize in the T-cell zone ina CCR7-dependent manner. Antigen presentation results in the activation of T cells, and effector T cells exit the lymph node through the

efferent lymphatics. B cells are recruited to the follicles, where CXCL13 (B-cell chemoattractant 1 [BCA-1]) is present.


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a key factor in asthma, in which the chemokine

CCL11 (eotaxin) and its receptor, CCR3, contrib-ute to the recruitment of eosinophils to the lung.

Psoriasis is another example of chemokine-medi-ated local cell recruitment and inflammation.

Infiltrating effector T cells express CCR4, and

its ligands (CCL17 and CCL22) are produced bycutaneous cells. CXCR3 has also been implicated

in the recruitment of T cells to inflamed skin.47

Multiple Sclerosis

Multiple sclerosis provides an informative exam-ple of the many levels at which chemokines caninfluence the progression and severity of an auto-

immune disease. Of the cells in the inflamma-tory infiltrate in actively demyelinating lesions,

10 percent are CD4+ and CD8+ T cells, and 90percent are macrophages derived from infiltrat-

ing monocytes and resident microglia. Interest intargeting the transport of leukocytes in the treat-ment of multiple sclerosis accelerated in late 2004,

after the Food and Drug Administration approvednatalizumab a humanized monoclonal anti-

body that blocks the 4 leukocyte integrins forthe treatment of the disease. This agent was sub-

sequently suspended because progressive multi-focal leukoencephalopathy occurred in three pa-tients receiving natalizumab. The efficacy of

natalizumab and the appearance of unexpectedadverse effects underline both the promise and

the challenges involved in the modification of

leukocyte transport for the treatment of inflam-matory diseases.

Analyses of chemokines and chemokine recep-tors in blood and cerebrospinal fluid and in brain

sections from patients with multiple sclerosis48have yielded complex data. The expression of

chemokine receptors on lymphocytes in bloodand cerebrospinal fluid is similar among patients

and controls49; most lymphocytes in cerebrospinalfluid in both groups are CD4+ memory T cells, in

proportions that are significantly higher than inblood.50 These lymphocytes in cerebrospinal fluidare uniformly CCR7+, and most of them express

CXCR3. Such findings suggest that there is sur-veillance of the central nervous system by CD4+

memory T cells, which patrol the subarachnoidspace in search of antigens and return to the

blood or the lymph nodes (Fig. 2).51 Recent stud-ies showed that CCR7 is important for the guid-

ance of CD4+ memory T cells both out of tissues

and into lymphatic organs.52,53

Patients with multiple sclerosis consistently

have lower levels of CCL2 in cerebrospinal fluidthan do patients with noninflammatory neuro-

logic disorders, and these levels are lower still at

times of clinically or radiographically active dis-ease. The levels of CCL2 in the cerebrospinal

fluid of persons with many other neuroinflam-matory conditions, including stroke and HIV-

associated encephalopathy, are usually higher thanthe levels in patients with multiple sclerosis.54,55

Other inf lammatory chemokines, such as CXCL10,are elevated during the active phases of multiplesclerosis.55 A plausible reason for the low CCL2

levels in the cerebrospinal fluid of patients withmultiple sclerosis is that CCL2 is consumed by

circulating mononuclear cells that bear CCR2,the major receptor for CCL2.56

T cells expressing CXCR3 are readily found inmultiple sclerosis lesions near parenchymal ves-sels (Fig. 2), but the expression of CCR7 in these

activated effector cells is down-regulated.55,57 In-filtrating monocytes in the lesions are derived

from a subpopulation of blood monocytes andexpress both CCR1 and CCR5.58,59 Phagocytic

macrophages do not express CCR1 but are CCR5-positive. Many ligands for these receptors CXCL10, CCL2, CCL3, CCL4, CCL5, and CCL8

are also present in multiple sclerosis lesions.These findings suggest that chemokines regulate

monocytes and macrophages by governing their

departure from the bloodstream into tissues,their migration through lesions, and their effec-tor functions. Assigning roles to individual recep-tors is critical to the identification of relevant

targets for drugs in development and will assistin the design of clinical trials.

Metabolic Disorders

Atherosclerosis

Fatty streaks, the hallmark of early atheroscle-rotic lesions, consist of lipid-laden macrophages(foam cells). In nonhuman primates,60 mono-

cytes circulating in the blood are the precursorsof foam cells (Fig. 3 and the animated figure of

the Supplementary Appendix, available with thefull text of this article at www.nejm.org). CCL2 is

present in these macrophage-rich atheroscleroticplaques,61,62 and minimally oxidized low-density


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lipoprotein (LDL) cholesterol, but not native LDL

cholesterol, induces the production of CCL2 inendothelial and smooth-muscle cells. CCL2 has

thus emerged as a link between oxidized lipopro-teins and the recruitment of foam cells to the

vessel wall. Studies in mice in which either CCL2

or CCR2 was genetically deleted provide strongsupport for this hypothesis: the deletion of CCL2

attenuated diet-induced atherosclerosis,63,64 andthe deletion of CCR2 in mice with a deficiency of

apolipoprotein E that were fed a high-fat diet pre-vented the accumulation of macrophages and the

formation of atherosclerotic lesions.65 In contrast,mice with a deficiency of CCR5, which is activatedby CCL3, CCL4, and CCL5 but not CCL2, remained

vulnerable to atherosclerosis.66

A polymorphism in the promoter of CCL2 (the

substitution of G for A at position 2518) hasbeen associated with increased transcription of

the CCL2 gene,67 and patients who were homozy-gous for the polymorphism were found at higherrisk for coronary artery disease than patients who

were heterozygous.68 Another polymorphism ofCCR2, in which the valine at amino acid 64 in

the first transmembrane domain is replaced withisoleucine (V64I), has been identif ied, but its rela-

tion to coronary artery disease is unclear.69,70CXCR271 and CX

3CR172,73 have also been impli-

cated in the early formation of atheroma. A poly-

morphism in CX3CR1, the CX

3CL1 receptor, con-

fers protection against calcific atherosclerotic

lesions.69,74 An unanswered question is the extent

to which each chemokine acts either indepen-dently or in concert with other chemokines torecruit and activate monocytes and T cells with-in the atherosclerotic lesion.

Insulin Resistanceand Obesity-Induced Diabete s

The usual view of obesity is that the number offat cells (adipocytes) in adipose tissue is relative-

ly fixed these cells increase in size, but not innumber, when excess calories are consumed.Adipocytes have thus been viewed primarily as

fat-storage depots. In recent years, however, it hasbecome clear that adipocytes are metabolically

active. They secrete a family of cytokines referredto as adipokines.75,76 One of these adipokines,

TNF-, exacerbates insulin resistance by desensi-tizing insulin receptors. Adipose tissue containsnumerous macrophages, which provide a rich

source of TNF- and interleukin-6, consistent

with the view that adiposity is a form of chronic,low-grade inflammation.77,78

Cytokines and chemokines play important

roles in insulin resistance. Circulating levels ofC-reactive protein and interleukin-6 correlate with

the risk of type 2 diabetes.79 In mice, the geneticdeletion of TNF- or its receptor decreases obesity-

induced insulin resistance.80 Adipocytes express

Figure 2 (facing page). Chemokine Receptors in

Inflammation and Immune Surveillance of the CentralNervous System.

Tissue compartments of the central nervous system the choroid plexus, the lateral ventricle and subarach-

noid space, where cerebrospinal fluid (CSF) circulates,

and the brain parenchyma establish various connec-

tions to the peripheral immune system: the blood ves-sels and the deep cervical lymph nodes. In healthy per-

sons (Panel A), the bloodbrain barrier is intact, and

cells from the systemic circulation enter brain tissueinfrequently. In patients with inflammatory diseases

such as multiple sclerosis, connections from the im-

mune system to the central nervous system take vari-ous forms, including the entry of activated memory

T cells from the circulation and monocytes across a

disrupted bloodbrain barrier (Panel B) into the brainparenchyma. Cells entering the brain parenchyma are

initially found in perivascular infiltrates (Panel B) and

are mainly CCR1+ and CCR5+ monocytes, with a mi-

nority population of effector T cells, which expressCXCR3 but not CCR7. Deeper in the brain parenchyma

(Panel C), inflammatory macrophages down-regulateCCR1, retaining CCR5. Physiologic immune surveil-lance of the central nervous system is mediated by

memory T cells, which cross the bloodCSF barrier

(Panel D); this barrier is composed of tight junctionsamong epithelial cells of the choroid plexus. In healthy

persons, more than 75 percent of CSF cells (lateral

ventricle, Panel E) are CD4+ memory T cells express-ing CCR7, which facilitates their return to the lymph

nodes, and CXCR3, which indicates bias toward the ex-

pression of type 1 helper cy tokines such as interferon-.

Connections from the central nervous system to theimmune system are established when memory T cells

in the CSF exit with the fluid along olfactory nerve-

sheath filaments, across the cribriform plate, into lym-

phatics in the nasal mucosa, and then to deep cervicallymph nodes (Panel F). Interstitial fluid of the central

nervous system further drains into perivascular path-ways that are continuous with the VirchowRobin

space around cerebral arterioles (Panel A) or across

the nonbarrier ependymal cells that line the ventricles(Panel D), joining the CSF and carrying antigenic sol-

utes to cervical lymph nodes (Panel F) so that the CSF

is a partial functional equivalent of the lymph. There

are a few monocytes in the CSF (Panels D and E),derived from a subpopulation of CCR1+ and CCR5+

monocytes in the blood.


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CCR2,81 which when activated by CCL2, causesthe expression of inflammatory genes and im-

paired uptake of insulin-dependent glucose. Fur-thermore, adipocytes synthesize CCL2,81 creatingconditions for a positive autocrine-feedback loop

while also providing a potent signal for the re-cruitment of macrophages. Obese mice with a de-

ficiency of CCR2 have improved insulin resis-tance, which provides support for a potentiallyimportant role of CCL2 in the metabolic syn-


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drome.82 CCL3 is also up-regulated in adipocytesand may contribute to insulin resistance and mac-

rophage recruitment.81

T herapeut i c S t r at eg ies

During the past decade, we have witnessed the

development of potent agents to treat inf lamma-tion and autoimmune diseases. Monoclonal anti-

bodies that neutralize TNF-, a potent driver ofmany of the actions involved in leukocyte migra-

tion and inflammation, are effective in the treat-ment of rheumatoid arthritis.83 Monoclonal anti-bodies that block integrin-dependent leukocyte

adhesion, such as anti41, reduce inflammationin patients with multiple sclerosis and Crohns

disease.84,85 There is also intense interest in find-

ing a way to interrupt the interactions betweenchemokines and their receptors as a new methodto treat inflammation.

In practice, chemokine receptors have proved

difficult to antagonize, perhaps because of thelarge surface of interaction with the chemokine

ligand. The first chemokine receptors to betargeted were the HIV coreceptors, CCR5 and

CXCR4. Drugs that prevent the entry of HIV intocells by blocking CCR5 are being studied in late-

stage clinical trials and may soon be availablecommercially. Antagonists of a number of otherchemokine receptors are in phase 12 clinical

trials for the treatment of rheumatoid arthritis,multiple sclerosis, asthma, and allergic rhinitis

(Table 3). There is also considerable interest in

the use of a CCR2 antagonist for the treatmentof atherosclerosis, but the lack of suitable sur-

rogate clinical end points or well-validated bio-

markers has made it difficult to develop anti-inflammatory drugs to treat vascular disease.Clinical trials to evaluate whether the blockadeof CCR2 diminishes insulin resistance may be

more tractable. Other chemokine-receptor antag-onists are being targeted for the treatment of

asthma and allergic rhinitis (CCR3) and chronicobstructive pulmonary disease (CXCR1 and CXCR2)

and for stem-cell mobilization (CXCR4). Giventhe rapid progress that has been made in the

understanding of the movement of leukocytes toinflammatory sites, it is certain that continuedefforts will be made to develop specific chemo-

kine-receptor antagonists.

No potential conflict of interest relevant to this article wasreported.

Figure 3 (facing page). Recruitment of Monocytes

to Fatty-Streak Lesions.

Monocytes circulating in the blood bind to the vascu-

lar endothelium and enter the subendothelial space,where they accumulate lipids and differentiate into

macrophages and foam cells. Panel A illustrates the

movement of low-density lipoprotein (LDL) cholesterol

across the endothelium and the uptake of oxidized LDLcholesterol by macrophages and foam cells. Panel B

illustrates the arrest of monocytes by full-length CX3CL1

and the presentation of chemokines such as CXCL1by endothelial-cell proteoglycans. Monocytes are also

captured by the binding of 41 integrin to vascular-

cell adhesion molecule 1 (VCAM-1) after the activationof receptors by chemokines.

Table 3. Status of Chemokine-Receptor Antagonists in Development.*

ChemokineReceptor Clinical Indication

Trial Status and Sponsoras of Winter 20052006

CCR1 Rheumatoid arthritis Phase 2, PfizerPhase 1, MillenniumAventis

Multiple sclerosis Phase 2, Berlex

CCR2 Rheumatoid arthritis Phase 2b, MillenniumPhase 1, AstraZenecaPhase 1, Incyte

Type 2 diabetes Phase 1, Incyte

Multiple sclerosis Phase 2, MerckPhase 1, MillenniumPhase 1, Incyte

CCR3 Allergic rhinitis andasthma

Phase 2, Cambridge AntibodyTechnology

Phase 2, GlaxoSmithKline

CCR5 HIV Phase 3, PfizerPhase 2, Schering-Plough

CCR9 Inflammatory bowel

disease

Phase 2, ChemoCentryx

CXCR1, CXCR2 Chronic obstructivepulmonary disease

Phase 1, GlaxoSmithKline

CXCR3 Psoriasis Phase 2, TularikAmgen

CXCR4 Stem-cell mobilization Phase 3, AnorMED

* Preliminary reports for some of these clinical trials have been presented atmedical and scientific meetings. No peer-reviewed articles providing com-plete data have yet been published.


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We are indebted to Drs. Philip Murphy and Barrett Rollinsfor their critical reading of the manuscript, to Mr. John C.W.Carroll and Mr. Jack Hull for assistance with the figures, to Mr.

Stephen Ordway and Dr. Gary Howard for editorial assistance,and to Ms. Mijoung Chang for her assistance in the preparationof the manuscript.

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Te Many Role Od Chemokines and Chemokine Receptors in Inflammation

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