Title: Chemokines and Chemokine Receptors: Standing at the Crossroads of Immunobiology and Neurobiology
Abstract: There are several molecular entities common to the immune and nervous systems. Salient among them are the chemokines and their receptors, which play remarkably varied and potent roles in immunobiology and neurobioloogy. This review limns several illustrative examples and presents general principles of chemokine action that are manifest in both systems. These include the following: (1) chemokines tend equally to arrest cells and to make them move, in the process of positioning target cells with spatiotemporal precision; (2) signaling and nonsignaling receptors collaborate to adjust the chemokine environment for maximal efficacy; and (3) expression of a single chemokine receptor on circulating blood cells and parenchymal cells is often used to coordinate complex tissue responses. The challenge is to integrate knowledge of the roles of key receptors (as well as their ligands) into a coherent account of events during pathologic processes, in order to guide therapeutic development. There are several molecular entities common to the immune and nervous systems. Salient among them are the chemokines and their receptors, which play remarkably varied and potent roles in immunobiology and neurobioloogy. This review limns several illustrative examples and presents general principles of chemokine action that are manifest in both systems. These include the following: (1) chemokines tend equally to arrest cells and to make them move, in the process of positioning target cells with spatiotemporal precision; (2) signaling and nonsignaling receptors collaborate to adjust the chemokine environment for maximal efficacy; and (3) expression of a single chemokine receptor on circulating blood cells and parenchymal cells is often used to coordinate complex tissue responses. The challenge is to integrate knowledge of the roles of key receptors (as well as their ligands) into a coherent account of events during pathologic processes, in order to guide therapeutic development. The immune and nervous systems comprise a number of molecules shared in common. Such findings were not unexpected given the complexity of the immune and nervous systems, but the specific molecules and processes involved have often been fascinatingly surprising. Chemokines and their receptors are prominent examples of joint use by the immune and nervous systems, yet seemed initially to be completely devoted to assisting the function of the immune system. The chemokine universe is comprised of approximately 50 peptides and 20 receptors in humans, with homologs, orthologs, and related peptides in other vertebrate species (Charo and Ransohoff, 2006Charo I.F. Ransohoff R.M. The many roles of chemokines and chemokine receptors in inflammation.N. Engl. J. Med. 2006; 354: 610-621Crossref PubMed Scopus (1068) Google Scholar, Rot and von Andrian, 2004Rot A. von Andrian U.H. Chemokines in innate and adaptive host defense: Basic chemokinese grammar for immune cells.Annu. Rev. Immunol. 2004; 22: 891-928Crossref PubMed Scopus (631) Google Scholar). Chemokines are divided into families and signal to corresponding families of chemokine receptors (for example, CXC chemokine action is mediated by CXC chemokine receptors). Chemokine receptors are G protein-coupled receptors (GPCRs) and act specifically through pertussis toxin-sensitive Gαi components. Chemokine-specific GPCRs are drug targets, and the biotechnology and pharmaceutical industry has mounted substantial efforts to modulate chemokine receptor activity, heightening the medical importance of understanding how chemokines regulate inflammatory disease. First identified by their ability to mediate leukocyte chemoattraction in vitro, chemokines are now recognized to govern a wide array of leukocyte functions during inflammation and immunity. The numerical mismatch between chemokines and receptors makes it apparent that ligand-receptor relationships may not be simple, and this suspicion has proven to be accurate (Rot and von Andrian, 2004Rot A. von Andrian U.H. Chemokines in innate and adaptive host defense: Basic chemokinese grammar for immune cells.Annu. Rev. Immunol. 2004; 22: 891-928Crossref PubMed Scopus (631) Google Scholar). Several chemokine-receptor pairs are exclusive; for other chemokine receptors, responses can be elicited by as many as 10 individual ligands. Conversely, some chemokines can productively signal to as many as three receptors. There have been several excellent reviews detailing ligand-receptor relationships (Bacon et al., 2002Bacon K. Baggiolini M. Broxmeyer H. Horuk R. Lindley I. Mantovani A. Maysushima K. 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The remarkable versatility and functional flexibility of the chemokine system is conferred by (1) their large number; (2) their tightly regulated transcriptional expression; (3) their ability to interact with binding moieties (such as glycosaminoglycans or nonsignaling receptors) after secretion; and (4) their proteolytic processing (Ransohoff, 2003Ransohoff R.M. Snip-snip, kill-kill: Truncated SDF-1 and HIV-associated neurodegeneration.Nat. Neurosci. 2003; 6: 1009-1011Crossref PubMed Scopus (6) Google Scholar). Lending further plasticity for regulated expression, chemokine genes can be subject to copy-number polymorphism. Chemokine expression, particularly during inflammation, is primarily regulated by inducible transcription, followed by translation, secretion, and turnover. However, two chemokines (CXCL16; CX3CL1) are expressed as transmembrane components that are regulated by cleavage by members of the ADAM (a disintegrin and metalloprotease) family enzymes, at least for action at a distance as soluble chemoattractants. Membrane-bound CX3CL1 and CXCL16 can also serve as adhesion molecules for receptor-bearing cells. The chemokine ligand super-family is further partitioned into subgroups of the largest (CC chemokines; 28 members) and second largest (CXC chemokines; 16 members) families. Genomic organization helps to give order to this large super-family (Colobran et al., 2007Colobran R. Pujol-Borrell R. Armengol M.P. Juan M. The chemokine network. I. How the genomic organization of chemokines contains clues for deciphering their functional complexity.Clin. Exp. Immunol. 2007; 148: 208-217Crossref PubMed Scopus (45) Google Scholar). Most human CXC chemokines are encoded at chromosomal location 4q12-21, with the majority of CC chemokine found at 17q11-21, and these loci are often syntenic in other mammalian species. Chemokine subgroup members, encoded in multigene arrays, are functionally related. For example, CXCL9, CXCL10, and CXCL11 are three CXC-family, IFN-γ-inducible chemokines. These chemokines signal to a single receptor CXCR3 (which is regulated by the Th1 cell-associated transcription factor T-bet) and are clustered together separated by at most a few dozen kilobases. A similar array contains eosinophil-attracting eotaxin peptides CCL24 and CCL26, which are members of the CC family. "Solitary" chemokines, such as CXCL12 at Chr.10q11 and CXCL16 at 17p13 found outside multigene arrays, are noted to be paired exclusively with individual signaling receptors and to have distinct functions. With respect to CXCL9, CXCL10, and CXCL11, even though their genomic, structural, and in vitro functional similarities give an appearance of conspicuous redundancy, careful analysis of cells expressing engineered receptors demonstrated selective signaling pathways suggesting distinct functions (Colvin et al., 2004Colvin R.A. Campanella G.S. Sun J. Luster A.D. Intracellular domains of CXCR3 that mediate CXCL9, CXCL10, and CXCL11 function.J. Biol. Chem. 2004; 279: 30219-30227Crossref PubMed Scopus (83) Google Scholar). This concept was confirmed with the demonstration that CXCL9 played a crucial and nonredundant role in antitumor immunity (Gorbachev et al., 2007Gorbachev A.V. Kobayashi H. Kudo D. Tannenbaum C.S. Finke J.H. Shu S. Farber J.M. Fairchild R.L. CXC chemokine ligand 9/monokine induced by IFN-gamma production by tumor cells is critical for T cell-mediated suppression of cutaneous tumors.J. Immunol. 2007; 178: 2278-2286PubMed Google Scholar). Not surprisingly, the role of CXCR3 in T cell trafficking during Th1 cell immune responses has proven surprisingly subtle and intricate (Koch et al., 2009Koch M.A. Tucker-Heard G. Perdue N.R. Killebrew J.R. Urdahl K.B. Campbell D.J. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation.Nat. Immunol. 2009; 10: 595-602Crossref PubMed Scopus (330) Google Scholar, Lord et al., 2005Lord G. Rao R.M. Choe H. Sullivan B.M. Lichtman A.H. Luscinskas F.W. Glimcher L.H. T-bet is required for optimal pro-inflammatory CD4+ T cell trafficking.Blood. 2005; 85: 3412-3415Google Scholar, Liu et al., 2005Liu L. Callahan M.K. Huang D. Ransohoff R.M. Chemokine receptor CXCR3: An unexpected enigma.Curr. Top. Dev. Biol. 2005; 68: 149-181Crossref PubMed Scopus (93) Google Scholar, Liu et al., 2006bLiu L. Huang D. Matsui M. He T.T. Hu T. DeMartino J. Lu B. Gerard C. Ransohoff R.M. Severe disease, unaltered leukocyte migration, and reduced IFN-{gamma} production in CXCR3−/− mice with experimental autoimmune encephalomyelitis.J. Immunol. 2006; 176: 4399-4409PubMed Google Scholar). It is accordingly accurate to speak both of redundancy and specificity in the chemokine system (Mantovani, 1999Mantovani A. The chemokine system: Redundancy for robust outputs.Immunol. Today. 1999; 20: 254-257Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar, Charo and Ransohoff, 2006Charo I.F. Ransohoff R.M. The many roles of chemokines and chemokine receptors in inflammation.N. Engl. J. Med. 2006; 354: 610-621Crossref PubMed Scopus (1068) Google Scholar, Rot and von Andrian, 2004Rot A. von Andrian U.H. Chemokines in innate and adaptive host defense: Basic chemokinese grammar for immune cells.Annu. Rev. Immunol. 2004; 22: 891-928Crossref PubMed Scopus (631) Google Scholar). The eponymous action of chemokines toward responsive cells is gradient-dependent chemoattraction in vitro. It seems intuitively appealing to assign chemokines a role in leukocyte trafficking based purely on their ability to drive gradient-dependent migration; this notion, however, is incomplete. Rather, chemokine action causes cells initially to arrest, rather than move (Figure 1), during the multistep process of leukocyte extravasation (Butcher, 1991Butcher E.C. Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity.Cell. 1991; 67: 1033-1036Abstract Full Text PDF PubMed Google Scholar) under flow (Alon et al., 2003Alon R. Grabovsky V. Feigelson S. Chemokine induction of integrin adhesiveness on rolling and arrested leukocytes local signaling events or global stepwise activation?.Microcirculation. 2003; 10: 297-311Crossref PubMed Scopus (42) Google Scholar, Alon and Feigelson, 2002Alon R. Feigelson S. 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Chemokine-chemokine receptor signaling (or action through closely related chemoattractant receptors) is therefore essential for leukocyte-endothelial recognition, which regulates leukocyte trafficking. Leukocyte extravasation requires multiple chemokine-mediated signals. As noted above, the first signal, delivered by chemokines immobilized on the luminal surface of the endothelial cell, helps convert leukocyte rolling under flow on endothelium into arrest, by inducing Rho GTPase family signaling that causes conformational change and redistribution of leukointegrins (Ward, 2009Ward S.G. Millipede-like lymphocyte crawling: Feeling the way with filopodia.Immunity. 2009; 30: 315-317Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar). These alterations in their shape and distribution are required for firm adhesion of leukocyte integrins (such as LFA-1) to CAMs (such as ICAM-1) on endothelium (Shulman et al., 2009Shulman Z. Shinder V. Klein E. Grabovsky V. Yeger O. Geron E. Montresor A. Bolomini-Vittori M. Feigelson S.W. Kirchhausen T. et al.Lymphocyte crawling and transendothelial migration require chemokine triggering of high-affinity LFA-1 integrin.Immunity. 2009; 30: 384-396Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). Additional chemokine signals are implicated in "crawling" of leukocytes across endothelium in search of a suitable locus for extravasation. Finally, chemokines are implicated in extravasation itself through inducing cytoskeletal reorganization and chemotaxis toward abluminal chemokines in inflamed tissues. In one classic example, CCL21 is an arrest receptor for lymphocytes rolling on high endothelial venules (HEV) of peripheral lymph nodes (Stein et al., 2000Stein J.V. Rot A. Luo Y. Narasimhaswamy M. Nakano H. Gunn M.D. Matsuzawa A. Quackenbush E.J. Dorf M.E. von Andrian U.H. The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules.J. Exp. Med. 2000; 191: 61-76Crossref PubMed Scopus (288) Google Scholar). In the context of leukocyte trafficking, chemokines and their receptors are grouped as homeostatic (chemokines expressed constitutively in organs such as in lymph nodes and spleen, with receptors on leukocytes homing to those organs) or inflammatory (chemokines induced on-demand at sites of inflammation, with cognate receptors on infiltrating leukocytes) (Charo and Ransohoff, 2006Charo I.F. Ransohoff R.M. The many roles of chemokines and chemokine receptors in inflammation.N. Engl. J. Med. 2006; 354: 610-621Crossref PubMed Scopus (1068) Google Scholar). As predicted, gene targeting studies showed that inflammatory chemokine receptors such as CCR2 and CXCR2 are essential for responses to a wide variety of infectious and inflammatory challenges (Charo and Ransohoff, 2006Charo I.F. Ransohoff R.M. The many roles of chemokines and chemokine receptors in inflammation.N. Engl. J. Med. 2006; 354: 610-621Crossref PubMed Scopus (1068) Google Scholar). Studies of the homeostatic chemokine receptors such as CCR7 and CXCR5 led to a paradigm refinement (if not shift): in early gene-targeting experiments, CXCR5 (Forster et al., 1996Forster R. Mattis A.E. Kremmer E. Wolf E. Brem G. Lipp M. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen.Cell. 1996; 87: 1037-1047Abstract Full Text Full Text PDF PubMed Scopus (683) Google Scholar), and later CCR7, were implicated in developmental organogenesis for lymphoid tissues, as well as in lymphocyte homing to lymph nodes (Lipp and Muller, 2003Lipp M. Muller G. Shaping up adaptive immunity: The impact of CCR7 and CXCR5 on lymphocyte trafficking.Verh. Dtsch. Ges. Pathol. 2003; 87: 90-101PubMed Google Scholar). These striking findings showed chemokine receptors mediated cell migration during development, as well as during inflammatory and immune processes in the postnatal organism. Considerable effort seems to have been devoted to maintenance of appropriate fluid and tissue amounts of chemokines (Figure 2). For example, there are several chemokine receptor-like molecules (D6; duffy antigen receptor for chemokines: DARC; CCX-CKR; CCRL2; and possibly CXCR7) whose primary function seems to be adjusting ambient concentrations of their chemokine ligands (Locati et al., 2005Locati M. Torre Y.M. Galliera E. Bonecchi R. Bodduluri H. Vago G. Vecchi A. Mantovani A. Silent chemoattractant receptors: D6 as a decoy and scavenger receptor for inflammatory CC chemokines.Cytokine Growth Factor Rev. 2005; 16: 679-686Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, Mantovani et al., 2006Mantovani A. Bonecchi R. Locati M. Tuning inflammation and immunity by chemoattractant decoy receptors: The sound of silence.Nat. Rev. Immunol. 2006; 6: 907-918Crossref PubMed Scopus (203) Google Scholar). In some cases, these receptor-like molecules do not signal by the canonical GPCR pathways but rather internalize chemokines either to translocate them elsewhere or to dispose of them. From evaluation of chemokine receptor-deficient mice, it is now apparent that the "signaling" receptors similarly modulate the chemokine environment (Cardona et al., 2008Cardona A.E. Sasse M.E. Mizutani M. Cardona S.M. Liu L. Savarin C. Hu T. Ransohoff R.M. Scavenging roles of chemokine receptors: Chemokine receptor deficiency is associated with increased levels of ligand in circulation and tissues.Blood. 2008; 112: 256-263Crossref PubMed Scopus (55) Google Scholar, Mantovani and Locati, 2008Mantovani A. Locati M. Housekeeping by chemokine scavenging.Blood. 2008; 112: 215-216Crossref PubMed Scopus (3) Google Scholar). This function of chemokine receptors will need to be taken into account, as therapeutic chemokine receptor blockade becomes a more prevalent treatment for disease (Charo and Ransohoff, 2006Charo I.F. Ransohoff R.M. The many roles of chemokines and chemokine receptors in inflammation.N. Engl. J. Med. 2006; 354: 610-621Crossref PubMed Scopus (1068) Google Scholar). The chemokine receptor-like molecules that lack G protein coupling mediate important functions in chemokine biology (Rot and von Andrian, 2004Rot A. von Andrian U.H. Chemokines in innate and adaptive host defense: Basic chemokinese grammar for immune cells.Annu. Rev. Immunol. 2004; 22: 891-928Crossref PubMed Scopus (631) Google Scholar). By convention, these molecules, which fail to mediate chemoattraction in vitro and do not increase cytoplasmic calcium concentrations, are termed "nonsignaling" receptors, although they clearly couple the presence of their ligands to cellular responses. The nonsignaling receptors are closely related to chemokine receptors, being "seven-spanning" plasma membrane components. The best characterized are DARC and D6, each of which efficiently binds and internalizes numerous chemokines. Expressed on postcapillary venular endothelium, DARC supports leukocyte recruitment to tissues, through binding inflammatory chemokines abluminally, and internalizing them for transcytosis and immobilization on the lumenal aspect of the capillary, to signal to rolling leukocytes (Pruenster et al., 2009Pruenster M. Mudde L. Bombosi P. Dimitrova S. Zsak M. Middleton J. Richmond A. Graham G.J. Segerer S. Nibbs R.J. Rot A. The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity.Nat. Immunol. 2009; 10: 101-108Crossref PubMed Scopus (88) Google Scholar). Parenthetically, DARC has also been widely studied for its role in Plasmodium vivax invasion of erythrocytes (Horuk et al., 1993Horuk R. Chitnis C.E. Darbonne W.C. Colby T.J. Rybicki A. Hadley T.J. Miller L.H. A receptor for the malarial parasite Plasmodium vivax: The erythrocyte chemokine receptor.Science. 1993; 261: 1182-1184Crossref PubMed Google Scholar). On red cells, DARC has long been proposed to carry out physiological scavenging of the unbound plasma fraction of its approximate dozen of chemokine ligands. This speculation was confirmed with the recent demonstration that posttransfusion pulmonary inflammation is caused in part by the loss of DARC's scavenging activity on banked erythrocytes (Mangalmurti et al., 2009Mangalmurti N.S. Xiong Z. Hulver M. Ranganathan M. Liu X.H. Oriss T. Fitzpatrick M. Rubin M. Triulzi D. Choi A. Lee J.S. Loss of red cell chemokine scavenging promotes transfusion-related lung inflammation.Blood. 2009; 113: 1158-1166Crossref PubMed Scopus (58) Google Scholar). DARC therefore plays an exquisitely subtle role in inflammation, removing surplus plasma chemokines that could mediate harmful, indiscriminate inflammation, while orchestrating leukocyte entry into tissues harboring pathogens or sites of damage. Encoded at human 3p21, near a cluster of chemokine receptor genes, D6 binds at least 12 inflammatory CC chemokines, internalizes them, and targets them for degradation, through constitutive recycling between plasma membrane and endocytic vesicles at an extraordinarily rapid rate (Locati et al., 2005Locati M. Torre Y.M. Galliera E. Bonecchi R. Bodduluri H. Vago G. Vecchi A. Mantovani A. Silent chemoattractant receptors: D6 as a decoy and scavenger receptor for inflammatory CC chemokines.Cytokine Growth Factor Rev. 2005; 16: 679-686Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). D6 is expressed constitutively on lymphatic endothelium and, inducibly, on leukocytes (Graham and McKimmie, 2006Graham G.J. McKimmie C.S. Chemokine scavenging by D6: A movable feast?.Trends Immunol. 2006; 27: 381-386Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar), and the functional importance of D6 on leukocytes versus lymphatic endothelium is an unresolved question (Graham and McKimmie, 2006Graham G.J. McKimmie C.S. Chemokine scavenging by D6: A movable feast?.Trends Immunol. 2006; 27: 381-386Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Topical phorbol ester or intradermal complete Freund's adjuvant (CFA) caused remarkably enhanced and sustained inflammation of the skin of D6-deficient mice, because of persistently elevated local chemokine concentrations (Martinez de la Torre et al., 2005Martinez de la Torre Y. Locati M. Buracchi C. Dupor J. Cook D.N. Bonecchi R. Nebuloni M. Rukavina D. Vago L. Vecchi A. et al.Increased inflammation in mice deficient for the chemokine decoy receptor D6.Eur. J. 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We speculated that D6-deficient mice might show a worsened course of EAE, if chemokine clearance from the CNS were impaired. Unexpectedly, D6-deficient mice did not generate efficient encephalitogenic responses to immunization with MOG35-55 peptide-CFA (complete Freund's adjuvant) and were relatively resistant to EAE (Liu et al., 2006aLiu L. Graham G.J. Damodaran A. Hu T. Lira S.A. Sasse M. Canasto-Chibuque C. Cook D.N. Ransohoff R.M. Cutting edge: The silent chemokine receptor d6 is required for generating T cell responses that mediate experimental autoimmune encephalomyelitis.J. Immunol. 2006; 177: 17-21PubMed Google Scholar), possibly because dendritic cells (DCs) trying to access lymphatics were trapped in the "hyperinflamed" immunization site. The role of D6 in immunity might therefore be to remove inflammatory chemokines and allow DCs exiting tissue to respond to homeostatic chemokine present on the lymphatic endothelial lumen. It should be emphasized that the D6 story is far from complete: the functional significance of its expression on lymphatic endothelium and leukocytes remains enigmatic, as does its physiological significance in adjusting the chemokine environment in the diverse settings (inflammation, cancer, pregnancy) in which it's been accorded physiological significance (Borroni et al., 2008Borroni E.M. Bonecchi R. Buracchi C. Savino B. Mantovani A. Locati M. Chemokine decoy receptors: New players in reproductive immunology.Immunol. Invest. 2008; 37: 483-497Crossref PubMed Scopus (12) Google Scholar, Borroni et al., 2009Borroni E.M. Buracchi C. Savino B. Pasqualini F. Russo R.C. Nebuloni M. Bonecchi R. Mantovani A. Locati M. Role of the chemokine scavenger receptor D6 in balancing inflammation and immune activation.Methods Enzymol. 2009; 460: 231-243Crossref PubMed Scopus (5) Google Scholar, Martinez de la Torre et al., 2007Martinez de la Torre Y. Buracchi C. Borroni E.M. Dupor J. Bonecchi R. 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Contribution of Duffy antigen to chemokine function.Cytokine Growth Factor Rev. 2005; 16: 687-694Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). The CNS is immune privileged by virtue of lacking resident DCs (Galea et al., 2007Galea I. Bechmann I. Perry V.H. What is immune privilege (not)?.Trends Immunol. 2007; 28: 12-18Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar). Equally important for the preservation of its postmitotic and fragile cells, the CNS possesses attributes that modify inflammation. These characteristics include the blood-brain barrier (BBB) (Bechmann et al., 2007Bechmann I. Galea I. Perry V.H. What is the blood-brain barrier (not)?.Trends Immunol. 2007; 28: 5-11Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar) and a tendency to recruit hematogenous cells very carefully. Cell loss after administration of the excitotoxin kainic acid (KA) involves neuronal necrosis and illustrates this principle: different to such injury in peripheral tissues (where necrotic injury elicits a rapid cellular response dominated by neutrophils), CNS leukocyte infiltrates after KA appear after a delay and consist primarily of mononuclear phagocytes (Bell and Perry, 1995Bell M.D. Perry V.H. Adhesion molecule expression on murine cerebral endothelium following the injection of a proinflammagen or during acute neuronal degeneration.J. Neurocytol. 1995; 24: 695-710Crossref PubMed Scopus (56) Google Scholar). If we consider the phenomenon of stringent control over leukocyte entry into the CNS (Engelhardt and Ransohoff, 2005Engelhardt B. Ransohoff R.M. The ins and outs of T-lymphocyte trafficking to the CNS: Anatomical sites and molecular mechanisms.Trends Immunol. 2005; 26: 485-495Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar) and also take account of the importance of chemokines for specificity in leukocyte migration, it