Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce? Carine Savarin-Vuaillat* and Richard M. Ransohoff*† *Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, and †Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Summary: Chemokines and chemokine receptors comprise a specific expression in A␤ plaques, may be a marker for Alzheimer large number of molecules implicated in a wide range of physio- pathology. Downregulation of CCL2 in cerebrospinal fluid may be logical and pathological functions. Numerous studies have dem- a candidate to characterize multiple sclerosis (MS), but needs onstrated the roles of chemokines and chemokine receptors: 1) additional investigation. Moreover, chemokines and chemokine during development, by regulating hematopoiesis, cardiogenesis, receptors represent interesting therapeutic targets. Using chemo- and vascular and cerebellar development; 2) during tumor biology, kine receptor antagonists, several studies provided exciting find- by controlling cell proliferation, angiogenesis, and metastasis; and ings for potential neurological disease treatment. Chemokine re- 3), especially during leukocyte migration, by acting on firm ad- ceptor antagonists reduce disease severity in animal models of hesion, locomotion, diapedesis, and chemotaxis. This review fo- MS. In glioblastoma, a CXCR4 antagonist (AMD3100) showed cuses on chemokine and chemokine receptor involvement in di- an inhibition of tumor growth. Inhibition of chemokine recep- verse neurological diseases and their therapeutic potentials. tor signaling is not the only therapeutic strategy: for exam- Because of its induction or upregulation during CNS pathologies, ple, CXCR4–CXCL12 has anti-inflammatory properties and members of the chemokine system can be used as biological CX3CL1–CX3CR1 controls neurotoxicity. Thus, chemokine markers. CXCR4 and CXCL12, by the correlation between their biology suggests several approaches for treating neurologi- expression and the glioblastoma tumor progression, could be a cal disease. Key Words: Chemokines, chemokine receptors, marker to grade this type of CNS tumor. CCR1, by virtue of neurological disease, cell trafficking, marker, antagonist. INTRODUCTION kine receptors have been described. Chemokine recep- tors are defined by selective, high-affinity ligand binding Chemokines—the term is a contraction of chemotactic coupled with demonstrable biological activity (usually cytokines—comprise a large family of small (8–14 kDa) chemotaxis or calcium mobilization). basic proteins that display a wide variety of biological and pathological functions. In vitro, the signature assay for chemokines involves stimulation of leukocyte che- Chemokines motaxis in a concentration-dependent manner. The first The complexity of the chemokine family is due to the chemokine to be described was IL8 (CXCL8), identified large number of component molecules. Moreover, add- in 1987 as a molecule with selective neutrophil chemoat- ing confusion to complexity, rapid discovery of new tractant properties.1 Since then, the chemokine family chemokines resulted in various research groups calling steadily expanded, now including more than 50 mole- the same molecule by different names. This unmanage- cules. Chemokines act by binding to G-protein-coupled able situation motivated a consortium, at the Keystone Symposium on Chemokine and Chemokine Receptors in cell-surface receptors on target cells. The first chemokine 3 receptor (IL8–CXCL8 receptor) was discovered in 1999, to create a systematic nomenclature. 1991.2 In parallel with their ligands, the interest in che- Chemokines are classified into four subfamilies ac- mokine receptors has grown and now nearly 20 chemo- cording to the configuration of two positionally con- served cysteine residues near the NH2 terminus. These include the CXC; CC; C; and CX3C subfamilies4,5 (FIG. 1)(http://cytokine.medic.kumamoto-u.ac.jp/CFC/CK/ Address correspondence and reprint requests to: Richard M. Ranso- hoff, Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail: Chemokine.html). [email protected]. The CXC and CC chemokines are the two major sub- 590 Vol. 4, 590–601, October 2007 © The American Society for Experimental NeuroTherapeutics, Inc. CHEMOKINE BIOLOGY IN NEUROLOGICAL DISEASE 591 FIG. 1. Chemokine nomenclature. Neurotherapeutics, Vol. 4, No. 4, 2007 592 SAVARIN-VUAILLAT AND RANSOHOFF families. The largest consists of CC chemokines, which Chemokine receptors are characterized by the adjacent position of the first two Chemokines exert their biological functions by binding to cysteine residues. CC subfamily members have a large seven-transmembrane-domain G-protein-coupled receptors spectrum of action and can attract monocytes, eosino- on target cells. The chemokine and chemokine receptor phils, basophils, T lymphocytes, natural killer (NK) nomenclatures are correlated, in that receptors that bind CC cells, and dendritic cells. This heterogeneity also extends chemokines (for example) are termed CC, followed by ‘R’ to their protein sequences and chromosome localization for receptor and a number that denotes the order of cloning. which allow for an informal categorization of this sub- Thus, the chemokine receptor family comprises the CC family into various groups, including allergenic (or (CCR1–10), CXC (CXCR1–7), XCR1 and CX3CR1 recep- MCP–eotaxin), inflammatory, HCC (hemofiltrate CC tors (FIG. 2). Chemokine specificity is largely restricted to receptors belonging to the same subgroup. In each sub- chemokine), developmental, and homeostatic sub- group, however, individual chemokines can bind more than groups.5 The MCP–eotaxin subgroup includes CCL2 one chemokine receptor just as single chemokine receptors (MCP1), the most extensively studied CC chemokine6 can be activated by diverse chemokines. There are isolated (FIG. 1). instances of monogamous chemokine–chemokine receptor The CXC chemokines are characterized by the inter- pairs: CXCL13–CXCR5, CXCL16–CXCR6, CCL1– position of a single amino acid (X) between their first CCR8, CCL25–CCR9, and CX3CL1–CX3CR19 (FIG. 2). two cysteine residues. This CXC subfamily can be sub- The expression of chemokine receptors is heteroge- classified into two other groups, depending on the pres- neous and is not restricted to hematopoietic cells. As ence or absence of the sequence motif glutamic acid– with their ligands, chemokine receptor expression can be leucine–arginine (ELR) near the N-terminus (FIG. 1). constitutive or inducible, but also downregulated by ex- This structural characteristic of CXC chemokines pro- posure to ligand or to activating and differentiating stim- vides a functional correlation: those containing the ELR uli (FIG. 3). Moreover, some chemokine receptors are motif bind and activate CXCR2, providing specificity for widely expressed, whereas others are restricted to certain neutrophils and other CXCR2-positive cells, whereas specific cells or by specific activation or differentiation those without the ELR motif have poor chemotactic abil- states.4 ity for neutrophils and act primarily on lymphocytes and The activation of chemokine receptors is induced by monocytes. the recognition and binding of their ligands. Based Unlike these two major subfamilies, the C and CX3C partly on analogy with other peptide ligands for G- chemokines contain two members and one member, re- protein-coupled receptors, the initial recognition be- spectively. The C chemokines, which comprise XCL1 tween chemokines and their receptors implicates ex- ␤ and XCL2, are distinguished from the other chemokine posed loops between the -strands of the chemokine subfamilies by the presence of only two of the four fold and the chemokine receptor extracellular protrud- 7 ing regions. Next, the N terminal region of the che- conserved cysteine residues. C chemokines can act on 10 lymphocytes, but not on neutrophils or monocytes. mokine initiates the activation of the receptor, which The sole CX3C chemokine is CX3CL1 (fractalkine). is followed by the internalization of the complex. G proteins are then activated, driving dissociation of CX3CL1 is characterized by the presence of three amino their heterotrimers into ␣ and ␤␥ subunits. Next, var- acids between the first two cysteine residues and also by ious signaling cascade effectors are activated, includ- an extended C-terminal sequence including a mucin-like ing phospholipase C (PLC), MAP kinases, or phos- domain and transmembrane and cytoplasmic regions. 11,12 phatidyl inositol-3OH kinase (PI-3K), which leads According to these structural features, CX3CL1 can be 8 to functional outcomes induced by chemokine receptor soluble as well as membrane-bound and acts as an ad- signaling (FIG. 3). hesion molecule or a chemoattractant for T cells, NK Chemokine receptor activation and signaling are cells, and mononuclear phagocytes. strictly controlled by desensitization, which prevents In parallel to this conventional nomenclature, many overstimulation of cells and inappropriate response12,13 chemokines can be broadly classified into two functional (FIG. 3). Chemokine receptor desensitization implies a groups. The first group comprises the homeostatic che- multistep process and a complex of proteins, including mokines, which are expressed constitutively and gener- G-protein-coupled receptor kinases (GRKs) and ␤-ar- ally involved in lymphoid organ development