This is a review article from this week's NEJM..it appears quite interesting and comprehensive(at least for those of us who are not immunologists!)..I've not read it thoroughly..it appears to be relevant for some of our bio's?
The Many Roles of Chemokines and Chemokine Receptors in Inflammation
New England Journal of Medicine Volume 354:610-621 February 9, 2006 Number 6
Israel F. Charo, M.D., Ph.D., and Richard M. Ransohoff, M.D.
Chemokines (chemotactic cytokines) are small heparin-binding proteins that direct the movement of circulating leukocytes to sites of inflammation or injury. During the eight years since chemokines and chemokine receptors were last reviewed in the Journal,1 a vast expansion in the understanding of chemokine biology has occurred. Originally studied because of their role in inflammation, chemokines and their receptors are now known to play a crucial part in directing the movement of mononuclear cells throughout the body, engendering the adaptive immune response and contributing to the pathogenesis of a variety of diseases. Chemokine receptors are some of the most tractable drug targets in the huge battery of molecules that regulate inflammation and immunity. For this reason, clinical trials involving chemokine-receptor antagonists for the treatment of inflammatory conditions have recently begun. In this review, we survey the properties of chemokines and their receptors and highlight the roles of these chemoattractants in selected clinical disorders.
The approximately 50 human chemokines segregate into four families on the basis of differences in structure and function (Table 1 and Table 2).1,2,3,4,5 A systematic nomenclature has been adopted in the past several years.6,7 The largest family consists 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 mononuclear cells to sites of chronic inflammation. The most thoroughly characterized CC chemokine is monocyte chemoattractant protein 1 (MCP-1), termed "chemokine ligand CCL2" in the systematic nomenclature. It is a potent agonist for monocytes, dendritic cells, memory T cells, and basophils. Other CC chemokines include macrophage inflammatory protein (MIP)-1 (CCL3), MIP-1 (CCL4), and RANTES (CCL5). It is likely that dimers or even tetramers are the active form of many CC chemokines.8
View this table:
[in this window]
[in a new window]
Table 1. CC Family of Chemokines and Chemokine Receptors.
View this table:
[in this window]
[in a new window]
Table 2. CXC, CX3C, and XC Families of Chemokines and Chemokine Receptors.
A second family of chemokines consists of CXC chemokines, which have a single amino acid residue interposed between the first two canonical cysteines. Some CXC chemokines, of which interleukin-8 (CXCL8) is the prototype, attract polymorphonuclear leukocytes to sites of acute inflammation. CXCL8 also activates 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 and transmembrane and cytoplasmic regions, thereby forming a cell-adhesion receptor capable of arresting cells under physiologic flow conditions.13,14 An enzyme, tumor necrosis factor (TNF)-–converting enzyme, can cleave CX3CL1 from the cell 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 antigen-presenting cells and T cells. CXCL16 also has scavenger-receptor activity for oxidized lipids containing phosphatidylserine and may participate 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-transmembrane–domain G-protein–coupled receptors; leukocyte responses to particular chemokines are determined by their complement of chemokine receptors. The binding of the chemokine to the receptor activates signaling cascades that culminate in the rearrangement, change of shape, and cell movement of actin. Unlike other chemokine receptors, CXCR4 is expressed in many tissues, including those of the central nervous system. In mice, the targeted deletion of CXCR4 or its ligand, CXCL12, causes perinatal death, indicating that this ligand and its receptor have a vital developmental function.21,22
Chemokines, Chemokine Receptors, and Innate Immunity
The ELR+ CXC Chemokines
A subfamily of CXC chemokines that have a characteristic glutamate–leucine–arginine (ELR) motif near the N terminal of the molecule are chemoattractants of neutrophils and contribute to wound repair. CXC chemokines (designated ELR+), such as CXCL8, bind the neutrophil receptors CXCR1 and CXCR2 to each other.23 ELR+ CXC chemokines are encoded in a multigene array on chromosome 4. A key function of ELR+ CXC chemokines is to attract neutrophils to sites of inflammation and induce granule exocytosis and the respiratory burst. Mediators of inflammation, including interleukin-1 and TNF-, or bacterial products such as lipopolysaccharide elicit the production of ELR+ CXC chemokines. It is clear that ELR+ CXC chemokines orchestrate the early phases of wound healing, but why mammals have seven similar ELR+ CXC chemokines remains enigmatic — especially since unique functional roles have not been found for most of them.24,25
Both ELR– and ELR+ CXC chemokines have been linked to angiogenesis.26,27 Vascularization of the gastrointestinal tract is defective in mice lacking either CXCR4 or its ligand, CXCL12.28 CXCR2 appears on endothelial cells during wound healing,29 and wound epithelialization and neovascularization are considerably delayed in CXCR2-knockout mice.30 The medical implications of these findings are wide ranging. A blockade of CXCR1 or CXCR2 could inhibit excessive infiltration or activation of neutrophils during acute inflammatory processes.23 Modulation of the angiogenic action of ELR– or ELR+ CXC chemokines holds promise for cancer treatment.27
Different chemokine families may interact during the formation of blood vessels. Several chemokines without the ELR motif, including CXCL4 and the ligands for CXCR3, antagonize angiogenesis. It has been shown in model systems that chemokine-mediated antiangiogenic properties can antagonize cardinal angiogenic factors such as endothelial growth factor and basic fibroblast growth factor.27 Early production of ELR+ CXC chemokines might promote the formation of granulation tissue and the protection of wound sites by attracting neutrophils and by inducing fibroblast differentiation and angiogenesis, 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 mycobacterial infection, toxin exposure, and ischemia. These proteins consist of a group of related peptides — CCL2, CCL7, CCL8, and CCL13 — encoded on chromosome 17.31,32 As with the seven ELR+ CXC chemokines, distinct functional attributes of the four monocyte chemoattractant proteins have not been identified. CCR2 is the only known receptor for CCL2 and CCL13,33,34 whereas CCL8 binds to both CCR2 and CCR5 and CCL7 binds to CCR1, CCR2, and CCR3. Studies of knockout mice indicate that CCL2 has a nonredundant role in regulating the infiltration of monocytes during inflammation.31 Moreover, under a broad range of stimuli, CCL2- and CCR2-knockout mice exhibit deficient monocyte recruitment in virtually every tissue.34
Because monocyte chemoattractant proteins can attract basophils and eosinophils and induce degranulation of these cells, they probably participate in allergic reactions. Moreover, mice that have a deficiency of CCL2 have defects in the production by antigen-primed lymphocytes of the type 2 helper cytokines that are involved in the production of antibodies.35 Mice lacking the receptor 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 is integral to innate immune responses. In these responses, chemokines are secreted downstream of the cellular recognition of pathogen-associated molecules and the first wave of production of inflammatory cytokines, such as interleukin-1. Chemokines therefore couple the detection of pathogens with the infiltration of tissues by neutrophils and monocytes.
CCR7
CCR7 and its ligands link innate and adaptive immunity through their effects on interactions between T cells and dendritic cells. During innate immune responses, phagocytes and soluble factors rather nonspecifically eliminate or neutralize pathogens. By contrast, the adaptive immune responses generated by B cells and T cells have specificity and memory. Adaptive immunity begins in lymphoid organs, where mature dendritic cells or macrophages present immunogenic peptides to naive or memory T cells (Figure 1). This encounter is governed with remarkable precision by two chemokines, CCL19 and CCL21, and their receptor, CCR7.36,37,38 Once immature dendritic cells ingest antigen and become able to present antigen to T cells, they increase their display of CCR7.24 These CCR7+ dendritic cells enter lymph nodes through the afferent lymph or the bloodstream, using vessel-bound CCL19 and CCL21 to sense their destination. Naive or memory T cells enter through high endothelial venules, using the same receptors and cues. Once inside the lymph node, CCR7+ dendritic cells and T cells follow gradients of CCL19 and CCL21 in T-cell zones to find one another. Given the low likelihood that any individual dendritic cell will present the "right" immunogenic peptide to a particular T cell, this process must be repeated continuously and with high efficiency to increase the probability that clones of antigen-specific T cells will be activated.2
View larger version (82K):
[in this window]
[in a new window]
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. Mature dendritic cells express CCR7, and macrophages express CCR2. T cells and dendritic cells together localize in the T-cell zone in a 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.
Mice lacking CCR7 (through targeted gene deletion) or that have insufficient CCL19 or CCL21 (through naturally occurring mutation) have structurally disorganized lymph-node T-cell zones and are deficient in T-cell–dependent immunity.39 Another receptor–ligand pair, CXCR5 and CXCL13, establish and coordinate the B-cell zones of lymph nodes.39,40 After antigen binding, B cells up-regulate CCR7 and move to the boundaries between B-cell and T-cell zones to interact with helper T cells.41 These insights have medical importance, because the understanding of lymph-node function 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 immunotherapy, and the suppression of transplant rejection and autoimmune disorders.
Movement of Lymphocytes to Skin and Gut
After an immune response subsides, CCR7+ memory T cells continuously circulate through tissues and lymph nodes by way of the bloodstream. Many of these long-lived cells are specialized for defending the skin or gastrointestinal tract against pathogens, and they are directed to these sites by specific homing signatures.42,43 For skin, the signature on the leukocyte is the CCR4–cutaneous lymphocyte antigen 1 (CLA-1) pair, and for the gut, the signature on the leukocyte is CCR9–47 integrin. Binding partners for these molecules are in the target tissue. The signatures are imprinted on lymphocytes in draining lymph nodes, in which antigen-presenting cells direct lymphocytes to return to the organs in which they first encountered antigen.44 Each major organ system probably has a unique "area code" that consists of lymphocyte surface molecules and counter receptors on endothelial beds.2 Indeed, initial indicators of distinct leukocyte-homing determinants for the lungs, joints, and the brain have been found, but much work remains to be done, including 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 either CXCR4 (for T-cell–tropic strains) or CCR5 (for macrophage-tropic strains). The targeting of T cells and monocytes allows HIV-1 access to sanctuary sites throughout the body and also cripples the CD4+ T cells that orchestrate antiviral immunity.5,45,46 Compelling genetic evidence of the central role of CCR5 in the pathogenesis of HIV-1 came from the identification of multiply exposed but uninfected persons, who proved to be homozygous for a nonfunctional variant of CCR5. Drugs that target these chemokine receptors for HIV disease are currently in advanced-stage clinical trials.
Inflammatory Diseases
Chemokines have been implicated in a wide range of diseases with prominent inflammatory components. For example, elevated levels of CC chemokines, particularly CCL2, CCL3, and CCL5, in the joints of patients with rheumatoid arthritis coincide with the recruitment of monocytes and T cells into synovial tissues. Inflammation is also a key factor in asthma, in which the chemokine CCL11 (eotaxin) and its receptor, CCR3, contribute to the recruitment of eosinophils to the lung. Psoriasis is another example of chemokine-mediated local cell recruitment and inflammation. Infiltrating effector T cells express CCR4, and its ligands (CCL17 and CCL22) are produced by cutaneous cells. CXCR3 has also been implicated in the recruitment of T cells to inflamed skin.47
Multiple Sclerosis
Multiple sclerosis provides an informative example of the many levels at which chemokines can influence the progression and severity of an autoimmune disease. Of the cells in the inflammatory infiltrate in actively demyelinating lesions, 10 percent are CD4+ and CD8+ T cells, and 90 percent are macrophages derived from infiltrating monocytes and resident microglia. Interest in targeting the transport of leukocytes in the treatment of multiple sclerosis accelerated in late 2004, after the Food and Drug Administration approved natalizumab — a humanized monoclonal antibody that blocks the 4 leukocyte integrins — for the treatment of the disease. This agent was subsequently suspended because progressive multifocal leukoencephalopathy occurred in three patients receiving natalizumab. The efficacy of natalizumab and the appearance of unexpected adverse effects underline both the promise and the challenges involved in the modification of leukocyte transport for the treatment of inflammatory diseases.
Analyses of chemokines and chemokine receptors in blood and cerebrospinal fluid and in brain sections from patients with multiple sclerosis48 have yielded complex data. The expression of chemokine receptors on lymphocytes in blood and cerebrospinal fluid is similar among patients and controls49; most lymphocytes in cerebrospinal fluid in both groups are CD4+ memory T cells, in proportions that are significantly higher than in blood.50 These lymphocytes in cerebrospinal fluid are uniformly CCR7+, and most of them express CXCR3. Such findings suggest that there is surveillance of the central nervous system by CD4+ memory T cells, which patrol the subarachnoid space in search of antigens and return to the blood or the lymph nodes (Figure 2).51 Recent studies showed that CCR7 is important for the guidance of CD4+ memory T cells both out of tissues and into lymphatic organs.52,53
View larger version (86K):
[in this window]
[in a new window]
Figure 2. Chemokine Receptors in Inflammation and Immune Surveillance of the Central Nervous System.
Tissue compartments of the central nervous system — the choroid plexus, the lateral ventricle and subarachnoid space, where cerebrospinal fluid (CSF) circulates, and the brain parenchyma — establish various connections to the peripheral immune system: the blood vessels and the deep cervical lymph nodes. In healthy persons (Panel A), the blood–brain barrier is intact, and cells from the systemic circulation enter brain tissue infrequently. In patients with inflammatory diseases such as multiple sclerosis, connections from the immune system to the central nervous system take various forms, including the entry of activated memory T cells from the circulation and monocytes across a disrupted blood–brain barrier (Panel B) into the brain parenchyma. Cells entering the brain parenchyma are initially found in perivascular infiltrates (Panel B) and are mainly CCR1+ and CCR5+ monocytes, with a minority population of effector T cells, which express CXCR3 but not CCR7. Deeper in the brain parenchyma (Panel C), inflammatory macrophages down-regulate CCR1, retaining CCR5. Physiologic immune surveillance of the central nervous system is mediated by memory T cells, which cross the blood–CSF barrier (Panel D); this barrier is composed of tight junctions among 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 expressing CCR7, which facilitates their return to the lymph nodes, and CXCR3, which indicates bias toward the expression of type 1 helper cytokines such as interferon-. Connections from the central nervous system to the immune system are established when memory T cells in the CSF exit with the fluid along olfactory nerve-sheath filaments, across the cribriform plate, into lymphatics in the nasal mucosa, and then to deep cervical lymph nodes (Panel F). Interstitial fluid of the central nervous system further drains into perivascular pathways that are continuous with the Virchow–Robin space around cerebral arterioles (Panel A) or across the nonbarrier ependymal cells that line the ventricles (Panel D), joining the CSF and carrying antigenic solutes 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.
Patients with multiple sclerosis consistently have lower levels of CCL2 in cerebrospinal fluid than do patients with noninflammatory neurologic disorders, and these levels are lower still at times of clinically or radiographically active disease. The levels of CCL2 in the cerebrospinal fluid of persons with many other neuroinflammatory conditions, including stroke and HIV-associated encephalopathy, are usually higher than the levels in patients with multiple sclerosis.54,55 Other inflammatory chemokines, such as CXCL10, are elevated during the active phases of multiple sclerosis.55 A plausible reason for the low CCL2 levels in the cerebrospinal fluid of patients with multiple 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 in multiple sclerosis lesions near parenchymal vessels (Figure 2), but the expression of CCR7 in these activated effector cells is down-regulated.55,57 Infiltrating monocytes in the lesions are derived from a subpopulation of blood monocytes and express 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 effector functions. Assigning roles to individual receptors is critical to the identification of relevant targets for drugs in development and will assist in the design of clinical trials.
Metabolic Disorders
Atherosclerosis
Fatty streaks, the hallmark of early atherosclerotic lesions, consist of lipid-laden macrophages (foam cells). In nonhuman primates,60 monocytes circulating in the blood are the precursors of foam cells (Figure 3 and the animated figure of the Supplementary Appendix, available with the full text of this article at www.nejm.org). CCL2 is present in these macrophage-rich atherosclerotic plaques,61,62 and minimally oxidized low-density lipoprotein (LDL) cholesterol, but not native LDL cholesterol, induces the production of CCL2 in endothelial and smooth-muscle cells. CCL2 has thus emerged as a link between oxidized lipoproteins and the recruitment of foam cells to the vessel wall. Studies in mice in which either CCL2 or CCR2 was genetically deleted provide strong support for this hypothesis: the deletion of CCL2 attenuated diet-induced atherosclerosis,63,64 and the deletion of CCR2 in mice with a deficiency of apolipoprotein E that were fed a high-fat diet prevented the accumulation of macrophages and the formation of atherosclerotic lesions.65 In contrast, mice with a deficiency of CCR5, which is activated by CCL3, CCL4, and CCL5 but not CCL2, remained vulnerable to atherosclerosis.66
View larger version (78K):
[in this window]
[in a new window]
Figure 3. Recruitment of Monocytes to Fatty-Streak Lesions.
Monocytes circulating in the blood bind to the vascular 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 LDL cholesterol by macrophages and foam cells. Panel B illustrates the arrest of monocytes by full-length CX3CL1 and the presentation of chemokines such as CXCL1 by endothelial-cell proteoglycans. Monocytes are also captured by the binding of 41 integrin to vascular-cell adhesion molecule 1 (VCAM-1) after the activation of receptors by chemokines.
A polymorphism in the promoter of CCL2 (the substitution of G for A at position –2518) has been associated with increased transcription of the CCL2 gene,67 and patients who were homozygous for the polymorphism were found at higher risk for coronary artery disease than patients who were heterozygous.68 Another polymorphism of CCR2, in which the valine at amino acid 64 in the first transmembrane domain is replaced with isoleucine (V64I), has been identified, but its relation to coronary artery disease is unclear.69,70 CXCR271 and CX3CR172,73 have also been implicated in the early formation of atheroma. A polymorphism in CX3CR1, the CX3CL1 receptor, confers protection against calcific atherosclerotic lesions.69,74 An unanswered question is the extent to which each chemokine acts either independently or in concert with other chemokines to recruit and activate monocytes and T cells within the atherosclerotic lesion.
Insulin Resistance and Obesity-Induced Diabetes
The usual view of obesity is that the number of fat cells (adipocytes) in adipose tissue is relatively fixed — these cells increase in size, but not in number, when excess calories are consumed. Adipocytes have thus been viewed primarily as fat-storage depots. In recent years, however, it has become clear that adipocytes are metabolically active. They secrete a family of cytokines referred to as adipokines.75,76 One of these adipokines, TNF-, exacerbates insulin resistance by desensitizing insulin receptors. Adipose tissue contains numerous 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 of C-reactive protein and interleukin-6 correlate with the risk of type 2 diabetes.79 In mice, the genetic deletion of TNF- or its receptor decreases obesity-induced insulin resistance.80 Adipocytes express CCR2,81 which when activated by CCL2, causes the expression of inflammatory genes and impaired uptake of insulin-dependent glucose. Furthermore, adipocytes synthesize CCL2,81 creating conditions for a positive autocrine-feedback loop while also providing a potent signal for the recruitment of macrophages. Obese mice with a deficiency of CCR2 have improved insulin resistance, which provides support for a potentially important role of CCL2 in the metabolic syndrome.82 CCL3 is also up-regulated in adipocytes and may contribute to insulin resistance and macrophage recruitment.81
Therapeutic Strategies
During the past decade, we have witnessed the development of potent agents to treat inflammation and autoimmune diseases. Monoclonal antibodies that neutralize TNF-, a potent driver of many of the actions involved in leukocyte migration and inflammation, are effective in the treatment of rheumatoid arthritis.83 Monoclonal antibodies that block integrin-dependent leukocyte adhesion, such as anti–41, reduce inflammation in patients with multiple sclerosis and Crohn's disease.84,85 There is also intense interest in finding a way to interrupt the interactions between chemokines and their receptors as a new method to treat inflammation.
In practice, chemokine receptors have proved difficult to antagonize, perhaps because of the large surface of interaction with the chemokine ligand. The first chemokine receptors to be targeted were the HIV coreceptors, CCR5 and CXCR4. Drugs that prevent the entry of HIV into cells by blocking CCR5 are being studied in late-stage clinical trials and may soon be available commercially. Antagonists of a number of other chemokine receptors are in phase 1–2 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 treatment of atherosclerosis, but the lack of suitable surrogate clinical end points or well-validated biomarkers has made it difficult to develop antiinflammatory drugs to treat vascular disease. Clinical trials to evaluate whether the blockade of CCR2 diminishes insulin resistance may be more tractable. Other chemokine-receptor antagonists are being targeted for the treatment of asthma and allergic rhinitis (CCR3) and chronic obstructive pulmonary disease (CXCR1 and CXCR2) and for stem-cell mobilization (CXCR4). Given the rapid progress that has been made in the understanding of the movement of leukocytes to inflammatory sites, it is certain that continued efforts will be made to develop specific chemokine-receptor antagonists.
View this table:
[in this window]
[in a new window]
Table 3. Status of Chemokine-Receptor Antagonists in Development.
No potential conflict of interest relevant to this article was reported.
We are indebted to Drs. Philip Murphy and Barrett Rollins for 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 preparation of the manuscript.
Source Information
From the Gladstone Institute of Cardiovascular Disease and the Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco — both in San Francisco (I.F.C.); and the Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, the Mellen Center for MS Treatment and Research, and the Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland (R.M.R.).
Address reprint requests to Dr. Charo at the Gladstone Institute of Cardiovascular Disease, 1650 Owens St., San Francisco, CA 94158, or at icharo@gladstone.ucsf.edu; or to Dr. Ransohoff at the Department of Neurosciences, NC30, the Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, or at ransohr@ccf.org.
References
Luster AD. Chemokines -- chemotactic cytokines that mediate inflammation. N Engl J Med 1998;338:436-445. [Full Text]
Rot A, von Andrian UH. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol 2004;22:891-928. [CrossRef][ISI][Medline]
Handel TM, Domaille PJ. Heteronuclear (1 H, 13 C, 15 N) NMR assignments and solution structure of the monocyte chemoattractant protein-1 (MCP-1) dimer. Biochemistry 1996;35:6569-6584. [CrossRef][ISI][Medline]
Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 2005;23:127-159. [CrossRef][ISI][Medline]
Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001;2:108-115. [CrossRef][ISI][Medline]
Bacon K, Baggiolini M, Broxmeyer H, et al. Chemokine/chemokine receptor nomenclature. J Interferon Cytokine Res 2002;22:1067-1068. [CrossRef][ISI][Medline]
Murphy PM, Baggiolini M, Charo IF, et al. International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev 2000;52:145-176. [Abstract/Full Text]
Proudfoot AEI, Handel TM, Johnson Z, et al. Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proc Natl Acad Sci U S A 2003;100:1885-1890. [Abstract/Full Text]
Gerszten RE, Garcia-Zepeda EA, Lim Y-C, et al. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 1999;398:718-723. [CrossRef][ISI][Medline]
Huo Y, Weber C, Forlow SB, et al. The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. J Clin Invest 2001;108:1307-1314. [Abstract/Full Text]
Bazan JF, Bacon KB, Hardiman G, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature 1997;385:640-644. [CrossRef][ISI][Medline]
Pan Y, Lloyd C, Zhou H, et al. Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature 1997;387:611-617. [Erratum, Nature 1997;389:100.] [CrossRef][ISI][Medline]
Haskell CA, Cleary MD, Charo IF. Molecular uncoupling of fractalkine-mediated cell adhesion and signal transduction: rapid flow arrest of CX3CR1-expressing cells is independent of G-protein activation. J Biol Chem 1999;274:10053-10058. [Abstract/Full Text]
Fong AM, Robinson LA, Steeber DA, et al. Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow. J Exp Med 1998;188:1413-1419. [Abstract/Full Text]
Tsou C-L, Haskell CA, Charo IF. Tumor necrosis factor--converting enzyme mediates the inducible cleavage of fractalkine. J Biol Chem 2001;276:44622-44626. [Abstract/Full Text]
Garton KJ, Gough PJ, Blobel CP, et al. Tumor necrosis factor--converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem 2001;276:37993-38001. [Abstract/Full Text]
Matloubian M, David A, Engel S, Ryan JE, Cyster JG. A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo. Nat Immunol 2000;1:298-304. [CrossRef][ISI][Medline]
Shimaoka T, Kume N, Minami M, et al. Molecular cloning of a novel scavenger receptor for oxidized low density lipoprotein, SR-PSOX, on macrophages. J Biol Chem 2000;275:40663-40666. [Abstract/Full Text]
Wuttge DM, Zhou X, Sheikine Y, et al. CXCL16/SR-PSOX is an interferon--regulated chemokine and scavenger receptor expressed in atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2004;24:750-755. [Abstract/Full Text]
Kelner GS, Kennedy J, Bacon KB, et al. Lymphotactin: a cytokine that represents a new class of chemokine. Science 1994;266:1395-1399. [ISI][Medline]
Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998;393:595-599. [CrossRef][ISI][Medline]
Ma Q, Jones D, Borghesani PR, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A 1998;95:9448-9453. [Abstract/Full Text]
Baggiolini M. Chemokines in pathology and medicine. J Intern Med 2001;250:91-104. [CrossRef][ISI][Medline]
Mantovani A. The chemokine system: redundancy for robust outputs. Immunol Today 1999;20:254-257. [CrossRef][ISI][Medline]
Martins-Green M, Hanafusa H. The 9E3/CEF4 gene and its product the chicken chemotactic and angiogenic factor (cCAF): potential roles in wound healing and tumor development. Cytokine Growth Factor Rev 1997;8:221-232. [CrossRef][Medline]
Bikfalvi A. Platelet factor 4: an inhibitor of angiogenesis. Semin Thromb Hemost 2004;30:379-385. [CrossRef][ISI][Medline]
Strieter RM, Belperio JA, Phillips RJ, Keane MP. CXC chemokines in angiogenesis of cancer. Semin Cancer Biol 2004;14:195-200. [CrossRef][ISI][Medline]
Tachibana K, Hirota S, Iizasa H, et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 1998;393:591-594. [CrossRef][ISI][Medline]
Romagnani P, Lasagni L, Annunziato F, Serio M, Romagnani S. CXC chemokines: the regulatory link between inflammation and angiogenesis. Trends Immunol 2004;25:201-209. [CrossRef][ISI][Medline]
Devalaraja RM, Nanney LB, Du J, et al. Delayed wound healing in CXCR2 knockout mice. J Invest Dermatol 2000;115:234-244. [Erratum, J Invest Dermatol 2000;115:931.] [CrossRef][ISI][Medline]
Daly C, Rollins BJ. Monocyte chemoattractant protein-1 (CCL2) in inflammatory disease and adaptive immunity: therapeutic opportunities and controversies. Microcirculation 2003;10:247-257. [CrossRef][ISI][Medline]
Gu L, Tseng SC, Rollins BJ. Monocyte chemoattractant protein-1. Chem Immunol 1999;72:7-29. [Medline]
Charo IF. CCR2: from cloning to the creation of knockout mice. Chem Immunol 1999;72:30-41. [Medline]
Charo IF, Peters W. Chemokine receptor 2 (CCR2) in atherosclerosis, infectious diseases, and regulation of T-cell polarization. Microcirculation 2003;10:259-264. [CrossRef][ISI][Medline]
Gu L, Tseng S, Horner RM, Tam C, Loda M, Rollins BJ. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 2000;404:407-411. [CrossRef][ISI][Medline]
Cyster JG. Chemokines and cell migration in secondary lymphoid organs. Science 1999;286:2098-2102. [Abstract/Full Text]
Cyster JG. Lymphoid organ development and cell migration. Immunol Rev 2003;195:5-14. [CrossRef][ISI][Medline]
Sozzani S, Allavena P, Vecchi A, Mantovani A. Chemokines and dendritic cell traffic. J Clin Immunol 2000;20:151-160. [CrossRef][ISI][Medline]
Müller G, Höpken UE, Lipp M. The impact of CCR7 and CXCR5 on lymphoid organ development and systemic immunity. Immunol Rev 2003;195:117-135. [Erratum, Immunol Rev 2003;196:265.] [CrossRef][ISI][Medline]
Cyster JG, Ngo VN, Ekland EH, Gunn MD, Sedgwick JD, Ansel KM. Chemokines and B-cell homing to follicles. Curr Top Microbiol Immunol 1999;246:87-92. [ISI][Medline]
Reif K, Ekland EH, Ohl L, et al. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 2002;416:94-99. [CrossRef][ISI][Medline]
Campbell DJ, Kim CH, Butcher EC. Chemokines in the systemic organization of immunity. Immunol Rev 2003;195:58-71. [CrossRef][ISI][Medline]
Campbell JJ, Butcher EC. Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. Curr Opin Immunol 2000;12:336-341. [CrossRef][ISI][Medline]
Calzascia T, Masson F, Di Berardino-Besson W, et al. Homing phenotypes of tumor-specific CD8 T cells are predetermined at the tumor site by crosspresenting APCs. Immunity 2005;22:175-184. [CrossRef][ISI][Medline]
Horuk R. Chemokine receptors and HIV-1: the fusion of two major research fields. Immunol Today 1999;20:89-94. [CrossRef][ISI][Medline]
Seibert C, Sakmar TP. Small-molecule antagonists of CCR5 and CXCR4: a promising new class of anti-HIV-1 drugs. Curr Pharm Des 2004;10:2041-2062. [CrossRef][ISI][Medline]
Flier J, Boorsma DM, van Beek PJ, et al. Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation. J Pathol 2001;194:398-405. [CrossRef][ISI][Medline]
Trebst C, Ransohoff RM. Investigating chemokines and chemokine receptors in patients with multiple sclerosis. Arch Neurol 2001;58:1975-1980. [Abstract/Full Text]
Kivisäkk P, Trebst C, Liu Z, et al. T-cells in the cerebrospinal fluid express a similar repertoire of inflammatory chemokine receptors in the absence or presence of CNS inflammation: implications for CNS trafficking. Clin Exp Immunol 2002;129:510-518. [CrossRef][ISI][Medline]
Kivisäkk P, Mahad DJ, Callahan MK, et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A 2003;100:8389-8394. [Abstract/Full Text]
Ransohoff RM, Kivisäkk P, Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 2003;3:569-581. [CrossRef][ISI][Medline]
Debes GF, Arnold CN, Young AJ, et al. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat Immunol 2005;6:889-894. [CrossRef][ISI][Medline]
Bromley SK, Thomas SY, Luster AD. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat Immunol 2005;6:895-901. [CrossRef][ISI][Medline]
Mahad DJ, Ransohoff RM. The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Semin Immunol 2003;15:23-32. [CrossRef][ISI][Medline]
Sørensen TL, Tani M, Jensen J, et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 1999;103:807-815. [Abstract/Full Text]
Mahad D, Callahan MK, Williams KA, et al. Modulating CCR2 and CCL2 at the blood-brain barrier: relevance for multiple sclerosis pathogenesis. Brain 2006;129:212-223. [Abstract/Full Text]
Kivisäkk P, Mahad DJ, Callahan MK, et al. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann Neurol 2004;55:627-638. [CrossRef][ISI][Medline]
Mahad DJ, Trebst C, Kivisäkk P, et al. Expression of chemokine receptors CCR1 and CCR5 reflects differential activation of mononuclear phagocytes in pattern II and pattern III multiple sclerosis lesions. J Neuropathol Exp Neurol 2004;63:262-273. [ISI][Medline]
Trebst C, Sørensen TL, Kivisäkk P, et al. CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis. Am J Pathol 2001;159:1701-1710. [Abstract/Full Text]
Faggiotto A, Ross R, Harker L. Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation. Arteriosclerosis 1984;4:323-340. [Abstract/Full Text]
Nelken NA, Coughlin SR, Gordon D, Wilcox JN. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest 1991;88:1121-1127. [ISI][Medline]
Yu X, Dluz S, Graves DT, et al. Elevated expression of monocyte chemoattractant protein 1 by vascular smooth muscle cells in hypercholesterolemic primates. Proc Natl Acad Sci U S A 1992;89:6953-6957. [Abstract/Full Text]
Gu L, Okada Y, Clinton SK, et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 1998;2:275-281. [CrossRef][ISI][Medline]
Gosling J, Slaymaker S, Gu L, et al. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest 1999;103:773-778. [Abstract/Full Text]
Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998;394:894-897. [CrossRef][ISI][Medline]
Kuziel WA, Dawson TC, Quinones M, et al. CCR5 deficiency is not protective in the early stages of atherogenesis in apoE knockout mice. Atherosclerosis 2003;167:25-32. [CrossRef][ISI][Medline]
Rovin BH, Lu L, Saxena R. A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression. Biochem Biophys Res Commun 1999;259:344-348. [CrossRef][ISI][Medline]
Szalai C, Duba J, Prohászka Z, et al. Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD): coincidence of elevated Lp(a) and MCP-1 -2518 G/G genotype in CAD patients. Atherosclerosis 2001;158:233-239. [CrossRef][ISI][Medline]
Valdes AM, Wolfe ML, O'Brien EJ, et al. Val64Ile polymorphism in the C-C chemokine receptor 2 is associated with reduced coronary artery calcification. Arterioscler Thromb Vasc Biol 2002;22:1924-1928. [Abstract/Full Text]
González P, Alvarez R, Batalla A, et al. Genetic variation at the chemokine receptors CCR5/CCR2 in myocardial infarction. Genes Immun 2001;2:191-195. [CrossRef][ISI][Medline]
Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest 1998;101:353-363. [Abstract/Full Text]
Lesnik P, Haskell CA, Charo IF. Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis. J Clin Invest 2003;111:333-340. [Abstract/Full Text]
Combadière C, Potteaux S, Gao J-L, et al. Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation 2003;107:1009-1016. [Abstract/Full Text]
McDermott DH, Fong AM, Yang Q, et al. Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J Clin Invest 2003;111:1241-1250. [Abstract/Full Text]
Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000;106:473-481. [Full Text]
Friedman JM. The function of leptin in nutrition, weight, and physiology. Nutr Rev 2002;60:S1-S14.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796-1808. [Abstract/Full Text]
Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821-1830. [Abstract/Full Text]
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286:327-334. [Abstract/Full Text]
Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF- function. Nature 1997;389:610-614. [CrossRef][ISI][Medline]
Gerhardt CC, Romero IA, Cancello R, Camoin L, Strosberg AD. Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol 2001;175:81-92. [CrossRef][ISI][Medline]
Weisberg SP, Hunter D, Huber R, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest (in press).
Feldmann M, Brennan FM, Paleolog E, et al. Anti-TNF therapy of rheumatoid arthritis: what can we learn about chronic disease? Novartis Found Symp 2004;256:53-73. [Medline]
Chaudhuri A, Behan PO. Natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:1598-1599. [Full Text]
Lew EA, Stoffel EM. Natalizumab for active Crohn's disease. N Engl J Med 2003;348:1599-1599. [Full Text] |
