Chemokine and chemokine receptor expression in the central ...1)/13-26.pdf · Chemokine and chemokine receptor expression in the central nervous system Joseph Hesselgesser*,1 and

Review

Chemokine and chemokine receptor expression in thecentral nervous system

Joseph Hesselgesser*,1 and Richard Horuk1

1Department of Immunology, Berlex Biosciences, 15049 San Pablo Avenue, Richmond, California 94806, USA

A decade ago several new cytokines were described that orchestrated theactivation and migration of immune cells. These newly described cytokines, ofwhich interleukin-8 (IL-8) was a representative member, de®ned a novel groupof molecules called chemokines (chemotactic cytokines). Chemokines are lowmolecular weight, 8 ± 12 kDa, basic proteins that have been classi®ed into fourdistinct families, CXC, CC, C and CX3C, based on the position of their ®rst twoconserved cysteine residues. The expression and biological function ofchemokines along with their cognate receptors have been well described onvarious subsets of leukocytes. Only more recently have these molecules beendescribed on various cells within the central nervous system. These pro-in¯ammatory proteins have been implicated in a variety of diseases within thecentral nervous system from Multiple Sclerosis to AIDS dementia. Whilechemokines are likely to enhance the evolution of central nervous systemin¯ammatory disorders they also have other roles in normal brain function anddevelopment. This review summarizes the role of chemokines and theirreceptors in the normal and pathophysiological brain.

Keywords: chemokine; multiple sclerosis; Alzheimer's disease; AIDS demen-tia; HIV; neuron; astrocyte

Introduction

In contrast to the old style Westerns where theheroes always wore white hats and the villainsalways wore black, chemokines, which are small,soluble, basic proteins that help to orchestrate thehost immune response, can wear hats of either colordepending on the circumstances. Normally, chemo-kines play a bene®cial role in host defense byattracting and activating leukocytes to destroycellular invasion by pathogenic organisms. How-ever, sometimes chemokines can inappropriatelyactivate immune cells leading to in¯ammation andhost cell destruction that can culminate in auto-immune diseases such as multiple sclerosis.

Chemokines were originally de®ned as hostdefense proteins although now they are known tohave a variety of other functions, such as growthregulatory and angiogenic properties, that extendbeyond the traditional role in regulating leukocytemigration (Baggiolini, 1998; Luster, 1998). In ad-dition, chemokine receptors can play an important

role in the pathogenesis of several diseases includ-ing malaria (Barnwell et al, 1987; Horuk et al, 1993)and HIV-1 (Luster, 1998).

Chemokines have been classi®ed into four groupsdependent on the number and spacing of the ®rsttwo conserved cysteine residues CXC, CX3C, CC andC. The CXC chemokines include interleukin-8 (IL-8), melanoma growth stimulatory activity (MGSA),interferon-inducible protein-10 (IP-10) and stromalderived factor-1 (SDF-1), while the CC classincludes RANTES, monocyte chemotactic protein-1 (MCP-1) and the macrophage in¯ammatoryproteins-1 (MIP-1a,b). Fractalkine, which is chemo-tactic for T cells and monocytes, is the only memberof the CX3C chemokine group while lymphotactin,which is chemotactic for lymphocytes, is the sole Cchemokine representative so far identi®ed.

Each of the chemokines recognizes and inducesthe chemotaxis of a particular subset of leukocytes.For example, CXC chemokines, like IL-8 andMGSA, preferentially attract neutrophils and in-duce their activation by producing changes inneutrophil shape, transient increases in cellularcalcium concentration and the upregulation ofsurface adhesion proteins (Baggiolini and Clark,

*Correspondence: J HesselgesserReceived 2 June 1998; revised 28 August 1998; accepted1 September 1998

Journal of NeuroVirology (1999) 5, 13 ± 26ãhttp://www.jneurovirol.com

1999 Journal of NeuroVirology, Inc.

1992). Several members of this family such as SDF-1and IP-10 are important molecules involved inchronic in¯ammatory processes that involve acti-vated T lymphocytes. In general the CC chemokineshave no effects on neutrophils but can chemoattractother leukocytes. Eotaxin for example is a potenteosinophil chemoattractant and induces their de-granulation, while RANTES and MCP-1 are che-moattractants for T cells and monocytesrespectively (Schall, 1994).

The chemokines produce their biologic effects byinteracting with speci®c receptors on the cellsurface of their target cells (Horuk, 1994). Chemo-kine receptors are characterized by a heptahelicalstructure and belong to a superfamily of seventransmembrane domain proteins that are coupled toguanine nucleotide binding proteins (G-proteins)(Dohlman et al, 1991). So far 15 different chemokinereceptors have been cloned (Luster, 1998).

While chemokines play an important role in hostdefense it has become abundantly clear that theirexpression is not solely restricted to immune cells.For instance under pro-in¯ammatory conditionsmany cell types, including endothelial cells,smooth muscle cells, tumor cells, astrocytes, micro-glia, and neurons, can produce chemokines orinduce chemokine receptor expression. Once che-mokines are induced they form solid phasegradients by binding to extracellular matrix pro-teins like glycosaminoglycans that decorate the cellsurface of endothelial cells. These gradients thenattract immune cells which undergo selectinmediated rolling along endothelial cells followedby ®rm adherence to chemokine-induced CD11/18complexes. This process ®nally results in thediapedesis of leukocytes across the endothelialspace into the tissues (Adams and Shaw, 1994;Springer, 1994). In the tissue spaces immune cellshelp to clear away cellular debris and releaseenzymes to destroy pathogens and begin thereparative process. Sometimes, however, the im-mune system is inappropriately activated inducingtissue damage that results in the release of host selfantigens that are normally not seen by the immunesystem. These proteins are now seen as `foreign' bythe immune system and this results in the recruit-ment of another wave of immune cells. This viciouscycle of chronic immune responses results infurther tissue damage that is a hallmark of auto-immune diseases like multiple sclerosis.

Endothelial cell production of chemokines andreceptor expression

The human brain occasionally comes under attackby pathogens. The ®rst line of defense is the bloodbrain barrier which consists of nonreactive en-dothelial cells that form tight junctions withastrocytic foot processes. Once activated by pro-

in¯ammatory cytokines both the endothelial layerof the CNS and adjacent astrocytes can release anumber of chemokines. For example, stimulation ofendothelial cell cultures with IL-1a, IL-1b, TNF-a orIL-4 upregulates the expression of MCP-1 and MCP-4 (Rollins and Pober, 1991; Li et al, 1993; Garcia-Zepeda et al, 1996). IL-1 also upregulates the CCchemokines MIP-1a and RANTES (Chuluyan et al,1995) and the CXC chemokine MGSA (Murakami etal, 1995). RANTES production by endothelial cellscan be inhibited by IL-4 and IL-13 (Marfaing-Kokaet al, 1995). Both IFN-g and IL-4 can synergize withTNF-a and IL-1 to induce MCP-4 mRNA accumula-tion (Garcia-Zepeda et al, 1996). In addition, theTh1 cytokine IFN-g induces the expression of theCXC chemokines IP-10 and MIG (Piali et al, 1998)and regulates the production of RANTES byendothelial cells ion response to TNF-a (Marfaing-Koka et al, 1995). A very recently identi®edchemokine from the new CX3C branch is alsoexpressed on endothelium (Bazan et al, 1997). Thisnew chemokine, fractalkine (Bazan et al, 1997) orneurotactin (Pan et al, 1997), is expressed as amembrane bound chemokine. This chemokine isunique in that it appears to be `presented' toimmune cells on the end of a mucin stalk, mostprobably to gain better access to the circulation.Under other in¯ammatory conditions such as thoseobserved in the monkey model of HIV, SIV infectedmacaque brain endothelium can produce MIP-1a,b,MCP-3 and RANTES (Sasseville et al, 1996). Onceimmune cells enter the brain parachyma they canfurther secrete cytokines to stimulate resident CNScells and contribute to the pathologies of encepha-litis.

Endothelial cells have also been shown to expresschemokine receptors, notably DARC (Hadley et al,1994; Peiper et al, 1995; Horuk et al, 1997), CXCR4(Lavi et al, 1997; Gupta et al, 1998; Volin et al,1998), and CCR5 (Edinger et al, 1997b; Rottman etal, 1997). Endothelial cells treated with IFN-gdownregulate CXCR4 expression while IL-1b,TNF-a and LPS induce transient changes in CXCR4expression (Gupta et al, 1998). While the in vivosigni®cance of chemokine receptor expression onendothelium has not been clari®ed it seems clearthat CCR5 and CXCR4 expression could contributeto the spread of HIV into the CNS.

Endothelial cell produced chemokines help toinduce the migration of primary immune responsecells such as T lymphocytes, monocytes andneutrophils across the blood brain barrier and intothe brain. In fact it has been shown that CD4+ restingmemory T-cells can extravasate through endothelialmonolayers (Brezinschek et al, 1995). However, inthe absence of an appropriate stimuli the newlymigrated immune cells do not become activated.This has been most clearly demonstrated intransgenic animals that are induced to over expresscertain chemokines. For example overexpression of

Chemokine and chemokine receptors in the brainJ Hesselgesser and R Horuk

14

the mouse neutrophil chemoattractant KC (themouse equivalent of MGSA) in the CNS, under thecontrol of the MBP promoter, leads to an increasedmigration of neutrophils within the brain (Tani etal, 1996a). Interestingly, these animals had littleevidence of tissue damage since no `foreign' antigenwas presented. However, after chronic expressionof KC many mice developed neurological symptomswith postural instability and rigidity. This neurolo-gical manifestation occured at 40 days of age longafter maximal chemokine expression. Histopathol-ogy showed signs of microglial activation andblood-brain barrier disruption. Therefore afterprolonged exposure to high levels of chemokinesthere was a breakdown of the blood brain barrierand immune exposure to CNS speci®c antigens withsubsequent activation of resident microglia.

Astrocyte cell production of chemokines andreceptor expression

The second critical cell type in maintaining theblood brain barrier is the astrocyte. Like endothe-lium, astroyctes seem to express a wide array ofchemokines under various conditions. Astrocytesand astrocytoma cell lines can produce IL-8 (Aloisiet al, 1992; Desbaillets et al, 1997), RANTES(Barnes et al, 1996) and MCP-1 (Barna et al, 1994)in response to IL-1 or TNF-a. In a murine hepatitisvirus-induced demyelinating model, astrocytes canspeci®cally produce CRG-2 (murine IP-10) a potentT-cell chemoattractant (Lane et al, 1998). A numberof glioblastoma cell lines (Desbaillets et al, 1994;Takeshima et al, 1994) as well as human malignantglioma surgical specimens (Takeshima et al, 1994)can express MCP-1. MIP-1a and MIP-1b mRNAexpression has been detected in astrocytes from thecerebral cortex of individuals with HIV encephalitisbrains (Schmidtmayerova et al, 1996). Whileastrocytes express a number of chemokines underpro-in¯ammatory conditions they also secrete lowlevels of IL-8 under normal circumstances (Aloisi etal, 1992; Desbaillets et al, 1997).

There are a number of reports that demonstrateastrocyte expression of chemokine receptors. Forexample, murine astrocytes express CCR1 andmigrate in response to MIP-1a (Tanabe et al,1997a). The same cells express functional CXCR4receptors and migrate in response to SDF-1 (Tanabeet al, 1997b). Human fetal astrocytes in cell cultureexpress low amounts of CXCR4 that can bedramatically upregulated upon exposure to IL-1b(Hesselgesser unpublished data). Human fetal astro-cytes also express low amounts of CXCR2 (Hessel-gesser et al, 1997). The HIV-1 coreceptor CCR5 hasrecently been shown to be expressed on astrocytesin the hippocampus and cerebellum (Rottman et al,1997). Although the in vivo signi®cance of chemo-kine receptor expression on astrocytes remains to be

clari®ed it is possible that they could also contributeto the pathogenesis of HIV in the CNS.

Neuronal expression of chemokine receptors:a possible role in CNS development?

A variety of evidence suggests that cytokines playan important role as immunomodulators of the CNS(Cunningham et al, 1993). The best studied of theseis IL-1 which appears to play a critical role in themodulation of neurohormone and neurotransmitterrelease as well as in the induction of neuronalsprouting following CNS injury (Cunningham andDe Souza, 1993). These trophic effects of thecytokines are clearly dependent on their durationof exposure and concentration. With increasedexposure and at higher concentrations theseproteins become neurotoxic. A recent reportsuggests that IL-8 is a potential trophic factor(Araujo and Cotman, 1993). Treatment of hippo-campal neurons with 1 mg/ml dose of IL-8 in-creased their survival in culture by 200% overcontrol neurons. Our ®ndings that CXCR2 receptorsare present in hippocampal neurons (Figure 1)(Horuk et al, 1997) are compatible with the trophiceffects of IL-8 described above and suggest that theeffects of IL-8 are most likely mediated by speci®cbinding to CXCR2.

Recently, other chemokine receptors such asCXCR4 have been shown to be expressed inpyramidal neurons of the hippocampus and thedentate gyrus (Lavi et al, 1997). Variable amountsof CXCR4 staining was also present in amygdala,cingulate gyrus, thalamous, and dentate nucleus of

Figure 1 CXCR2 expression in the human hippocampus.Immunohistochemical detection of CXCR2 in dentate gyrus ofhuman hippocampus. CXCR2 antibodies (Chuntharapai et al,1994), mouse myeloma control antibodies, tissue preparationand immunohistochemistry were as previously described (Horuket al, 1997). Intense staining of pyramidal neurons within thepolymorphic layer. Granule cell bodies and their correspondingdendrites within the molecular layer are lightly positive forCXCR2 expression. (From Peiper et al, unpublished data).


15

the cerebellum (Lavi et al, 1997). Neurons insimilar regions of the hippocampus and cerebellumare also positive for CCR5 expression (Rottman etal, 1997). The observations in the human brainhave also been con®rmed in nonhuman primateswhere certain populations of pyramidal neurons ofthe hippocampus, dentate gyrus and cerebralcortex are also positive for CXCR4, CCR3 andCCR5 in macaque brains (Westmoreland et al,1998). A second report has also demonstratedCXCR4 and slight CCR3 staining of neurons inthe brains of rhesus macaques but no CCR5expression (Zhang et al, 1998).

In contrast to the studies described above, whichwere all carried out in adult CNS, there have nowbeen several reports that suggest that chemokinereceptors are present in fetal neurons suggesting arole in CNS development. Using standard neuronalculture techniques it was shown that neurons fromE17 ± 22 week fetal brains expressed CXCR2 but notCXCR1 or DARC (Hesselgesser et al, 1997). Inaddition hNT neurons, which are similar to im-mature post-mitotic cholinergic neurons that havenumerous neuronal characteristics also express anumber of chemokine receptors including CXCR2,CXCR4, CCR1 and CCR5 (Hesselgesser et al, 1997).These neuronal chemokine receptors bind theirchemokine ligands with high af®nity and based onchemotaxis assays are also biologically functional(Hesselgesser et al, 1997). Interestingly, data fromseveral groups have shown that hNT cells canbecome established into the rat CNS and integrateto form neural networks with existing neuronsfurther intimating that these cells are similar toimmature human neurons (Kleppner et al, 1995;Borlongan et al, 1997).

Given that chemokine receptors are expressed onimmature neurons and that chemokines are se-creted by astrocytes it is tempting to speculate thatthese molecules might play a role in neuronaldevelopment. Considerable evidence to supportthis idea was recently provided from studies withCXCR4 knockout mice. Comparison of the brainsfrom normal and CXCR4-de®cient mice revealedabnormalities in the architecture of the cerebellumcompared to normal mice (Ma et al, 1998; Zou et al,1998). Neurons from the external granule layer(EGL) prematurely migrated toward the internalgranule layer (IGL) and were positioned beneath thePurkinje cell layer or interspersed within the layer,a normally postnatal process (Ma et al, 1998; Zou etal, 1998). During normal development, neurons inthe EGL migrate from the germinal matrix surface ofthe cerebellum through the molecular and Purkinjecell layers to form the IGL. The development ofprecisely formed neural networks, or neuronalpatterning, is important for the proper function ofthe CNS ensuring neuronal cell to cell communica-tion through a system of correctly formed synapses.In the CXCR4-de®cient mice this orderly process is

severely disrupted by the premature migration andabnormal positional clustering of neurons despitethe presence of intact radial glia. Consistent withthese studies SDF-1 gene knockout mice alsoshowed a similar pattern of abnormal developmentof the cerebellum (Ma et al, 1998).

Thus, the work of Zou et al (1998) and Ma et al(1998) builds upon previous studies that havedemonstrated neuronal expression of CXCR4 andsuggests an important role for this receptor ligandpair in CNS development. What could this role be?Many possibilities suggest themselves. For exam-ple, there is compelling evidence for cross talkbetween chemoattractant receptors, i.e. signals fromone receptor could induce the phosphorylationstate of other receptors thus potentiating or inhibit-ing the normal function of other receptors. Further,CXCR4 could regulate EGL neuronal migration byinhibiting the ability of cells to respond to otherchemoattractant signals. In fact, it has been pre-viously shown that neurons migrate in response tochemokines (Hesselgesser et al, 1997; Bolin et al,1998). Alternatively, recent studies have demon-strated that SDF-1 can induce apoptosis in a humanneuronal cell line via CXCR4 (Hesselgesser et al,1998). Thus, CXCR4 could aide in the apoptoticelimination of cells that have undergone incorrectmigration in the CNS thus helping to ensure correctneuronal patterning.

Oligodendrocyte expression of chemokinereceptors

In all previous studies looking at chemokinereceptor expression of the CNS there has been noidenti®cation of speci®c staining of oligodendro-cytes in vitro or in vivo. However, Robinson et alhave recently reported that MGSA, and its rodentequivalent KC can, in conjunction with PDGF, actsynergistically as growth factors for oligodendrocyteprogenitor cells in vitro (Ransohoff, personal com-munication). Further, work from the same grouphas shown that the chemokine MGSA/KC isexpressed in astrocytes within the spinal cord in apattern similar to that of proliferating oligodendro-cyte precursor cells. If these observations arecon®rmed by in vivo studies in the brain it wouldlend further credence to the idea that chemokinesplay important roles in the developing CNS.

Microglial expression of chemokines andchemokine receptors

It has been postulated that circulating HIV-infectedimmune cells transmit HIV into the CNS, presum-ably by interaction with and infection of microgliacells. Given that chemokine receptors are corecep-tors for HIV and that microglia play an important


16

role in CNS in¯ammation these cells have comeunder close scrutiny in studies to determine themechanism of HIV spread in the CNS. MessangerRNA for a number of chemokines including MIP-1aand MIP-1b have been detected in microglia fromthe cerebral cortex of individuals with HIVencephalitis (Schmidtmayerova et al, 1996). In vitrostudies indicate that fetal brain microglial culturesstimulated with IL-1b, TNF-a, and LPS can produceMIP-1a, and MIP-1b (McManus et al, 1998).Activated microglia can also produce the CX3Cchemokine fractalkine/neurotactin in response toLPS (Pan et al, 1997). Microglia from SIV infectedmacaques can produce both CXC and CC chemo-kines including IP-10, MIP-1a,b, RANTES and MCP-3 (Sasseville et al, 1996).

In addition to chemokines migroglia frommacaques also express a number of chemokinereceptors including CXCR4, CCR3 and CCR5(Westmoreland et al, 1998). Immunohistochemicalstaining of human brain sections has revealed thatthe T-tropic HIV coreceptor CXCR4 is expressed onmicroglia (Lavi et al, 1997; Vallat et al, 1998) andfetal microglia cultures (Vallat et al, 1998). The M-tropic HIV coreceptors CCR3 and CCR5 are alsoexpressed on fetal microglia cultures (He et al,1997). Interestingly a combination of antibodiesand ligands to CCR3 and CCR5 have not been ableto abrogate M-tropic HIV infectivity of these cellssuggesting a possible role of other coreceptors(Ghorpade et al, 1998). Another candidate cor-eceptor CCR8 has been shown to be an HIVcoreceptor in vitro (Horuk et al, 1998) and brainderived HIV isolates appear to use CCR8 ef®cientlyfor HIV entry (Jinno et al, 1998). However, the invivo signi®cance of these ®ndings cannot beaddressed until there is a direct demonstration ofCCR8 expression in CNS cells and blockade of HIVentry by appropriate CCR8 receptor ligand(s). Arecent study has demonstrated that molecularclones of envelopes from HIV-1 isolates of infectedhuman brains could use several known coreceptorsmostly CCR5 but also CCR3 and CXCR4 as entrymolecules and also replicate readily in microglia(Shieh et al, 1998).

Why are chemokine receptors expressed on glialcells? What is their possible function? Glial cellscarry out numerous functions in the CNS andthese could potentially be aided by chemokines.For example glial cells act as a mechanicalsupport system for nerve cells and during devel-opment can serve to guide migrating neurons toform correctly de®ned networks. Chemokinescould aid this process by helping glial cells toform the scaffolding that guides migrating nervecells and outgrowing axons to their appropriatepositions during neuronal development. Glial cellsalso have a phagocytic function in the CNShelping to clear away debris that arises duringneuronal degeneration. Chemokines could aid and

abet this scavenger-like role of glial cells in muchthe same way that they direct tissue macrophagesto clean up dead cells and kill invading patho-genic organisms.

Chemokines and Alzheimers disease

To determine whether chemokines could be in-volved in pathologic processes and/or reparativeresponses in the CNS, brain obtained from patientswith neurodegenerative disorders has been ana-lyzed for chemokine receptor expression. Immuno-histochemical analysis of involved brain tissuesfrom patients with Alzheimer's disease (AD)revealed high level expression of CXCR2 receptorin the neuritic portion of plaques, surroundingdeposits of amyloid (Horuk et al, 1997). Thisimmunoreactivity was detected in regions of thediseased brain which under normal circumstancesshowed very low level expression (Figure 2). These®ndings were later con®rmed by another group alsoshowing hippocampal neuronal expression ofCXCR2 in AD plaques co-localizing b-amyloid(bA) ploypeptides (Xia et al, 1997).

It is interesting to note that bA peptides canpotentiate the IL-1b-induced secretion of IL-8 byastrocytes (Gitter et al, 1995). These data furthersuggest that IL-8, via activation of CXCR2 receptors,could be a potential trophic factor for hippocampalneurons and suggest the possibility that chemo-kines may play a role in reparative processes andthat their cognate receptors may be induced underthese circumstances. It is possible that undercertain pathophysiologic conditions, such as areobserved in Alzheimers disease, the over produc-tion of IL-8 by astrocytes leads to the activation ofCXCR2 receptors in the CNS that could contribute

Figure 2 CXCR2 expression in Alzheimer's disease brain.CXCR2 antibodies (Chuntharapai et al, 1994), mouse myelomacontrol antibodies, tissue preparation and immunohistochemis-try were as previously described (Horuk et al, 1997). Over-expression of CXCR2 within the hippocampus from AD brainsection. (From Peiper et al, unpublished data).


17

to abnormal neuronal growth in vivo. While lowlevels of IL-8 may be necessary for cell to cellcommunication in the CNS, over production of thischemokine could lead to an abnormal physiology.But it has yet to be proven if CXCR2 expression inneuritic plaques of AD is a cause or a consequenceof the disease. The study by Xia et al (1997) clearlystated that the number of CXCR2 positive plaquesdid not correlate to disease progression measuredover several years.

Recently we found a marked increase in CCR1expression in neurons of the entorhinal cortex andsomatic staining of hippocampal neurons of theCA1 and CA3 region (Halks-Miller and Hesselges-ser, unpublished data). However, we have not seenexpression of CCR1 in cortical or hippocampalneurons of normal age matched brain tissue (Halks-Miller and Hesselgesser, unpublished data). CCR1staining was also present in dystrophic processesaround senile plaques. Confocal microscopy showsthese processes to be neuro®lament positive andCD68 negative (Halks-Miller and Hesselgesser,unpublished data). These ®ndings suggest thatCCR1 is upregulated in affected neurons in indivi-duals with Alzheimers disease, perhaps in responseto the disease process.

Chemokines and Multiple Sclerosis

Multiple sclerosis is an autoimmune diseasemediated by T and B lymphocytes, and macro-phages, which results in extensive in¯ammation anddemyelination of the white matter (Ebers, 1986).Although the mechanisms responsible for causingthis immunologic damage in the CNS are stillunknown they are almost certainly mediated byin®ltrating leukocytes. Initial interactions betweeninvading T cells and monocytes in the CNS resultsin the production of cytokines such as TNF and IL-1.These cytokines induce a variety of effects includingthe upregulation of class II major histocompatabilitycomplex (MHC), cell adhesion glycoproteins, andthe release of pro-in¯ammatory molecules by macro-phages and activated microglia (Merrill, 1987).Although increased cell activation and upregulationof cell adhesion molecules are critical events in thepathogenesis of multiple sclerosis, recruitment ofadditional activated T cells and macrophages is alsoa signi®cant feature of the disease. It is likely that achemotactic gradient of immobilized chemokines,possibly bound to sulfated glycans (Strieter et al,1989) on the subendothelial matrix (Huber et al,1991), guides the directed ¯ow of these bloodleukocytes across the endothelium into the CNS.

A variety of evidence implicates chemokines inmultiple sclerosis. For instance in an experimentalallergic encephalitis (EAE) model of multiplesclerosis in the mouse mRNA levels for a numberof chemokines including, KC, IP-10, MIP-1a,

RANTES, MARC (murine MCP-3) and TCA-3(murine I-309) are upregulated in spinal cord duringthe course of disease (Godiska et al, 1995).Chemokine transcript levels are induced severaldays prior to the onset of clinical disease andsustained throughout disease progression (Godiskaet al, 1995). Co-localization studies demonstratedthat MIP-1a and RANTES were produced exclu-sively by in®ltrating leukocytes (Glabinski et al,1997; Miyagishi et al, 1997) and that parenchymalneuroepithelial cells produced JE, IP-10 and KC,that co-localized with GFAP positive astrocytes(Glabinski et al, 1997). There is also data demon-strating that MCP-1 is upregulated in a rat EAEmodel (Hulkower et al, 1993) and that it isexpressed in astrocytes during the acute phase ofmurine EAE (Ransohoff et al, 1993; Tani et al,1996b).

The CX3C chemokine, fractalkine/neurotactin isupregulated in activated microglia of murine EAE(Pan et al, 1997). The receptor for fractalkine/neurotactin, CX3CR1, is expressed in NK cells, andmonocytes and is upregulated during IL-2 expan-sion of CD4+ and CD8+ T lymphocytes (Imai et al,1997). Expression of the chemokine TCA-3 (murineI-309) has been shown to correlate with the ability ofproteolipid protein speci®c T-cell clones to mediateEAE (Kuchroo et al, 1993). In a recent study Karpusand Kennedy (1997) demonstrated that the chemo-kines MIP-1a and MCP-1 were differentially ex-pressed depending on the severity or progress ofdisease. In this study MIP-1a levels correlated withacute onset of disease and MCP-1 productioncorrelated with relapsing phases of the disease.Furthermore, antibodies to MIP-1a but not MCP-1were able to inhibit development of acute diseasebut not relapsing EAE. While antibodies to MCP-1did not inhibit the onset and acute phases of diseasethey were able to diminish the severity of relapsingdisease. Studies from another group have alsodemonstrated that the chemokines JE (murineMCP-1), RANTES, MIP-1a, IP-10 and KC are alsoupregulated in the spinal cord and brain during theacute stages and chronic relapse of murine EAE(Glabinski et al, 1997).

While the role of each speci®c chemokine inhuman MS, is uncertain it is likely that theseproteins probably work in concert to recruitimmune cells into the CNS. The upregulation ofMIP-1a, RANTES and MARC (murine MCP-3), theligands for CCR1 (Neote et al, 1993; Combadiere etal, 1995) and CRG-2 (murine IP-10) (Lane et al,1998) a ligand for CXCR3, probably serve to recruitT-cells and activate tissue macrophages that arecritical to disease progression and development ofpathology in the demyelinating mouse models.

Monocytes are likely to be attracted to MS lesionsby MCP-1 and I-309, or in EAE by TCA-3 (murine I-309) and JE (murine MCP-1). I-309/TCA-3 is aspeci®c ligand for CCR8 which is expressed on


18

monocytes (Roos et al, 1997; Tiffany et al, 1997).Recent in vitro studies show that TCA-3 can rescuethymic T-cells from apoptosis in response todexamethasone (Van Snick et al, 1996). It ispossible that overexpression of TCA-3, which isnormally present at very low levels, in EAE (or MS)could protect T-cells normally undergoing apopto-sis in the thymus. This would allow naive T-cells tobecome memory T-cells and contribute to CNSantigen spread as seen in MS.

During the onset of MS, speci®c T lymphocytesubsets and monocytes are recruited into the CNSby chemokines such as RANTES, IP-10 and MCP-1which are produced by activated endothelial cellsand astrocytes (Figure 3). A number of chemokinesincluding MIP-1a, b and IP-10 are produced by CD8+

T lymphocytes from MS patients that recognizeproteolipid protein derived peptides presented byHLA class I molecules (Biddison et al, 1997; Honmaet al, 1997). IP-10 is a potent chemoattractant foractivated CD4+ T lymphocytes and induces theirmigration and enhanced adhesion to the endothe-lium. This begins the cycle of chronic recruitmentof myelin-speci®c T cells (Biddison et al, 1998)which enhances the activation of B lymphocytes to

produce immunoglobulins that enhance the de-struction of the blood brain barrier.

Monocytes, in response to MCP-1, also cross theblood brain barrier where they can be induced todifferentiate into macrophages by certain cytokines.These tissue macrophages and resident microgliacan become activated by MIP-1a to produce TNF-aand be induced to destroy and phagositize maturemyelin by speci®c myelin antibodies. The localrelease of pro-in¯ammatory cytokines such as TNFfrom macrophages further accelerates the process ofastrocyte and endothelial cell production of che-mokines and adhesion molecules and contributes tothe vicious cycle of chronic in¯ammation.

On the positive side it is also possible thatchemokines could play a role in the remyelinationor reparative processes of MS. For example MIP-1acould serve a bene®cial function in recruitingmonocytes and macrophages to clear myelin debrisand thus allow oligodendrocyte progenitors toexpand and differentiate. Since KC is also upregu-lated in EAE this chemokine may be working as areparative factor to regenerate damaged neuronalprocesses and enhance oligodendrocyte prolifera-tion and remyelination, perhaps via CXCR2.

Figure 3 Schematic representation of chemokine action in MS brain. Several chemokines including IP-10 and RANTES are producedby astrocytes and activated endothelium to recruit T lymphocytes from the peripheral circulation to perivascular regions within thebrain. MCP-1 secretion by endothelium and cytokine stimulated astrocytes chemoattract and activate monocytes from circulation.Monocytes eventually extravasate and mature to macrophages which are then stimulated by MIP-1a and MIP-b, produced bysurrounding astrocytes, to secrete pro-in¯ammatory cytokines such as TNF and maintain the cycle of chronic in¯ammation.


19

Chemokine receptors in the CNS and HIV-1

Given the critical role of chemokines in hostdefense it is not surprising that chemokine recep-tors have themselves become portals of entry forpathogenic organisms. The human immunode®-ciency virus HIV-1 which has been shown torequire chemokine receptors as coreceptors forinfection (D'Souza and Harden, 1996).

CD4 was initially identi®ed as an entry factor forHIV-1. However, the fact that a small number ofhuman cells and the vast majority of non humancells resisted infection by the virus (Ashorn et al,1990; Dragic et al, 1992) raised the possibility thatother accessory molecules were involved in HIV-1infection and the search was on to ®nd these elusivecofactors. The ®rst clue to their identity wasprovided by Cocchi et al (1995) who showed thatthe chemokines MIP-1a, MIP-1b and RANTES couldblock viral infectivity in vitro. However, thesechemokines were only able to block viral infectivitymediated by macrophage-tropic (M-tropic) virusesand were without effect on T-cell line-tropic (T-tropic) strains of virus. Shortly after these studiesFeng et al (1996) demonstrated that a chemokinereceptor now known as CXCR4, the SDF-1 receptor,was able to act as a cofactor for viral fusion of T-tropic but not M-tropic strains of HIV-1. Later,several reports ¯ooded the literature with thediscovery of a chemokine receptor, CCR5, speci®cfor the chemokines MIP-1a, MIP-1b and RANTES(Samson et al, 1996) completed the circle and anumber of investigators were able to simulta-neously demonstrate that CCR5 was an entrycofactor for M-tropic isolates of HIV-1 (Alkhatib etal, 1996; Choe et al, 1996; Deng et al, 1996; Doranzet al, 1996; Dragic et al, 1996). Now severalchemokine receptors have been described forinfectivity by HIV-1 (He et al, 1997; Rucker et al,1997; Horuk et al, 1998; Jinno et al, 1998) and therelated viruses HIV-2 (Endres et al, 1996; Reeves etal, 1997), SIV (simian) (Deng et al, 1997; Edinger etal, 1997a, b; Farzan et al, 1997; Marcon et al, 1997)and FIV (feline) (Willett et al, 1997a, b; Hosie et al,1998).

Circulating monocytes and T lymphocytes alongwith resident brain macrophages and microglia arebelieved to be one of the major routes of viralspread into the CNS and contribute to thepathologies seen in pediatric AIDS or AIDSdementia. Endothelial cells and microglia are the®rst line of defense for the CNS. As these cellsbecome infected by HIV-1 from the circulation theycontribute to further CNS expansion. Once virusreplication has begun within the CNS, viral spreadcan occur by infection of reactive or ®brillaryastrocytes and in restricted cases neurons. It is nowaccepted that primary isolates of HIV-1 are dualtropic in nature, i.e. they can infect cells via CCR5mostly on macrophages (M-tropic) or non-syncytia-

inducing (NSI) and CXCR4 on T-lymphocytes (T-tropic) or syncytia-inducing (SI) (D'Souza andHarden, 1996). However, as the number of CCR5expressing cells in the body becomes low the virustends to use CXCR4 (Connor et al, 1997; Scarlatti etal, 1997).

It has been recently reported that SI strains ofHIV-1 will, slowly over time, up-regulate MIP-1aand RANTES (two of the ligands for CCR5) thuscontributing to the growth of SI strains that useCXCR4 and induce a switch in viral tropism that isseen in the later stages of AIDS (Glushakova et al,1997; Scarlatti et al, 1997). Some T-tropic strains ofHIV-1 and HIV-2 have also evolved to use CXCR4 inthe absence of CD4 (Hirka et al, 1991; Endres et al,1996) and could infect cells such as vascularendothelial cells (Lavi et al, 1997; Moses et al,1997), astrocytes and neurons (Hirka et al, 1991).Neurovirulent strains of SIV are also able to infectbrain capillary endothelial cells via CCR5, but in theabsence of CD4 (Edinger et al, 1997b).

Activated endothelial cells and astrocytes canproduce a number of chemokines that can attractinfected monocytes or T lymphocytes from circula-tion. These infected immune cells are able to crossthe blood brain barrier in response to the chemo-tactic gradient and enter the perivascular regions ofthe brain. Once in the brain the HIV infected cellsencounter resident microglia/macrophages. Theseresident immune cells express a number of chemo-kine receptors; CXCR4, CCR3, CCR5 (He et al, 1997;Lavi et al, 1997; Rottman et al, 1997). At this pointthe virus is able to use a number of chemokinereceptors expressed on microglia. In most HIVencephalitis cases there is a restricted infectivityof endothelial cells, astrocytes and neurons (re-viewed in Kolson and Pomerantz, 1996). Addition-ally granular staining of CXCR4 is seen inmultinucleated giant cells of HIV infected brains(Lavi et al, 1997) a hallmark of ADC. It seems clearthat the major source of continued viral replicationwithin the CNS is from invading immune cells andresident microglia. However, other contributingfactors to the pathology of ADC are due todisruptions in normal CNS functions of astroyctesand neurons. It is not necessary for these non-immune cell types to be directly infected by HIV;however viral proteins such as envelope, gp120, caninduce abnormal cellular functions.

Neuronal apoptosis is a feature of HIV-1 infectionwithin the brain (Adle-Biassette et al, 1995; Gelbardet al, 1995) although the exact mechanism(s) are notclearly understood. It is well documented thatgp120 can cause abnormal functions of astrocytesinducing the release of a number of cellularmetabolites and neurotoxic factors (Lipton et al,1991; Meucci and Miller, 1996 and reviewed inKolson and Pomerantz, 1996). Soluble gp120 canalso be toxic to primary neurons in vitro (Bagetta etal, 1995; Aggoun-Zouaoui et al, 1996) and cause


20

neuronal dysfunction and abnormal neuronalchanges in vivo (Corboy et al, 1992; Toggas et al,1994; Berrada et al, 1995). It has also beendemonstrated that direct interactions betweengp120 and neurons induces apoptosis even in theabsence of macrophages/microglia (Bagetta et al,1995; Aggoun-Zouaoui et al, 1996). A possiblemechanism for this could involve gp120 bindingto, and activation of, neuronal chemokine corecep-tors.

Human neurons express the coreceptors CCR5and CXCR4 (Lavi et al, 1997; Rottman et al, 1997).The neuronal cell line hNT also expresses func-tional CCR5 and CXCR4 receptors (Hesselgesser etal, 1997). Neurons are CD4 negative but can beinfected by HIV in a very restricted manner,however, this does not readily lead to productiveviral replication. T-tropic isolates of HIV-1 such asthose that occur late in AIDS have been shown toinfect hNT neurons in the absence of CD4 (Hirka etal, 1991). T-tropic gp120 can induce neuronalapoptosis in hNT cells by directly binding andactivating CXCR4 receptors (Hesselgesser et al,1997, 1998). In addition, the CXCR4 ligand SDF-1a

is also able to induce apoptosis in these cells(Hesselgesser et al, 1998). Along a similar veintwo recent studies have shown that HIV-1 and SIVenvelope proteins can activate CXCR4 and CCR5(Davis et al, 1997; Weissman et al, 1997). Takentogether these studies suggest that soluble gp120could mediate some of its CNS toxic effects directly,by binding to CXCR4 on neurons or even astrocytes.Direct activation of chemokine receptors on cellsoutside the immune system, speci®cally in the CNScould correlate to HIV CNS dysfunction andcontribute to the pathology seen in CNS AIDS.

Conclusions

Although chemokines and their cognate receptorsplay an active part in regulating the traf®cking ofimmune cells their expression throughout the CNS(Summary in Table 1) makes it abundantly clear thattheir role goes well beyond that. For example theireffects on non-immune cells, such as neurons, andoligodendrocytes are likely to be very differentand most probably include growth regulatory and

Table 1 Summary of chemokine and chemokine receptor expression by cells of the central nervous system and expression in variousdisease states.


21

developmental effects. Thus, even though chemo-kines can induce the chemotaxis of neurons in asimilar manner to that of leukocytes, their biologicalconsequences are very different, i.e. chemokines playan important role in neuronal migration during fetal

development. The role of chemokines and theirreceptors in the CNS are just beginning to be exploredand given the complexities of the CNS it is quiteprobable that further discoveries regarding chemo-kine function in the brain still await to surprise us.

References

Adams DH, Shaw S (1994). Leukocyte-endothelialinteractions and regulation of leukocyte migration.Lancet 343: 831 ± 836.

Adle-Biassette H, Levy Y, Colombel M, Poron F, NatchevS, Keohane C, Gray F (1995). Neuronal apoptosis inHIV infection in adults. Neuropathology & AppliedNeurobiology 21: 218 ± 227.

Aggoun-Zouaoui D, Charriaut-Marlangue C, Rivera S,Jorquera I, Ben-Ari Y, Represa A (1996). The HIV-1envelope protein gp120 induces neuronal apoptosis inhippocampal slices. Neuroreport 7: 433 ± 436.

Alkhatib G, Combadiere C, Broder CC, Feng Y, KennedyPE, Murphy PM, Berger EA (1996). CC CKRS: ARANTES, MIP-1a, MIP-1b receptor as a fusion cofactorfor macrophage-tropic HIV-1. Science 272: 1955 ±1958.

Aloisi F, Care A, Borsellino G, Gallo P, Rosa S, BassaniA, Cabibbo A, Testa U, Levi G, Peschle C (1992).Production of hemolymphopoietic cytokines (IL-6, IL-8, colony-stimulating factors) by normal humanastrocytes in response to IL-1 beta and tumor necrosisfactor-alpha. J Immunol 149, 2358 ± 2366.

Araujo DM, Cotman CW (1993). Trophic effects ofinterleukin-4, -7 and -8 on hippocampal neuronalcultures : potential involvement of glial-derived fac-tors. Brain Res 600: 49 ± 55.

Ashorn PA, Berger EA, Moss B (1990). Human immuno-de®ciency virus envelope glycoprotein/CD4-mediatedfusion of nonprimate cells with human cell. J Virol64: 2149 ± 2156.

Bagetta G, Corasaniti MT, Berliocchi L, Navarra M,Finazzi-Agro A, Nistico G (1995). HIV-1 gp120produces DNA fragmentation in the cerebral cortexof rat. Biochem Biophys Res Commun 211: 130 ± 136.

Baggiolini M (1998). Chemokines and leukocyte traf®c.Nature 392: 565 ± 568.

Baggiolini M, Clark-Lewis I (1992) Interleukin-8, achemotactic and in¯ammatory cytokine. FEBS Letters307: 97 ± 101.

Barna BP, Pettay J, Barnett GH, Zhou P, Iwasaki K, EstesML (1994). Regulation of monocyte chemoattractantprotein-1 expression in adult human non-neoplasticastrocytes is sensitive to tumor necrosis factor (TNF)or antibody to the 55-kDa TNF receptor. J Neuroim-munology 50: 101 ± 107.

Barnes DA, Huston M, Holmes R, Benveniste EN, YongVW, Scholz P, Perez HD (1996). Induction of RANTESexpression by astrocytes and astrocytoma cell lines. JNeuroimmunol 71, 207 ± 214.

Barnwell JW, Nichols ME, Rubenstein P (1987). In vitroevaluation of the role of the Duffy blood group inerythrocyte invasion by Plasmodium vivax. J Exp Med169: 1795 ± 1802.

Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, RossiD, Greaves DR, Zlotnik A, Schall TJ (1997). A newclass of membrane-bound chemokine with a CX3Cmotif. Nature 385: 640 ± 644.

Berrada F, Ma D, Michaud J, Doucet G, Giroux L,Kessous-Elbaz A (1995). Neuronal expression of hu-man immunode®ciency virus type 1 env proteins intransgenic mice: distribution in the central nervoussystem and pathological alterations. J Virol 69: 6770 ±6778.

Biddison WE, Cruikshank WW, Center DM, Pelfrey CM,Taub DD, Turner RV (1998). CD8+ myelin peptide-speci®c T cells can chemoattract CD4+ myelinpeptide-speci®c T cells: importance of IFN-inducibleprotein 10. J Immunol 160: 444 ± 448.

Biddison WE, Taub DD, Cruikshank WW, Center DM,Connor EW, Honma K (1997). Chemokine and matrixmetalloproteinase secretion by myelin proteolipidprotein-speci®c CD8+ T cells: potential roles inin¯ammation. J Immunol 158: 3046 ± 3053.

Bolin LM, Murray R, Lukacs NW, Strieter RM, KunkelSL, Schall TJ, Bacon KB (1998). Primary sensoryneurons migrate in response to the chemokineRANTES. J Neuroimmunol 81: 49 ± 57.

Borlongan CV, Koutouzis TK, Jorden JR, Martinez R,Rodriguez AI, Poulos SG, Freeman TB, McKeown P,Cahill DW, Nishino H, Sanberg PR (1997). Neuraltransplantation as an experimental treatment modalityfor cerebral ischemia. Neurosci Biobehav Rev 21: 79 ±90.

Brezinschek RI, Lipsky PE, Galea P, Vita R, Oppenhei-mer-Marks N (1995). Phenotypic characterization ofCD4+ T cells that exhibit a transendothelial migratorycapacity. J Immunol 154: 3062 ± 3077.

Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, PonathPD, Wu LJ, Mackay CR, LaRosa G, Newman W,Gerard N, Gerard C, Sodroski J (1996). The b-chemokine receptors CCR3 and CCR5 facilitate infec-tion by primary HIV-1 isolates. Cell, 85: 1135 ± 1148.

Chuluyan HE, Schall TJ, Yoshimura T, Issekutz AC(1995). IL-1 activation of endothelium supports VLA-4(CD49d/CD29)-mediated monocyte transendothelialmigration to C5a, MIP-1 alpha, RANTES, and PAFbut inhibits migration to MCP-1: A regulatory role forendothelium-derived MCP-1. Journal of LeukocyteBiology 58: 71 ± 79.

Chuntharapai A, Lee J, Hebert CA, Kim KJ (1994).Monoclonal antibodies detect different distributionpatterns of IL-8 receptor A and IL-8 receptor B onhuman peripheral blood leukocytes. J Immunol 153:5682 ± 5688.

Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, GalloRC, Lusso P (1995). Identi®cation of RANTES, MIP-1a,and MIP-1b as the major HIV-suppressive factorsproduced by CD8+ T cells. Science, 270: 1811 ± 1815.

Combadiere C, Ahuja SK, Van Damme J, Tiffany HL, GaoJL, Murphy PM (1995). Monocyte chemoattractantprotein-3 is a functional ligand for CC chemokinereceptors 1 and 2B. J Biol Chem 270: 29671 ± 29675.


22

Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR(1997). Change in coreceptor use correlates withdisease progression in HIV-1 infected individuals. JExp Med 185: 621 ± 628.

Corboy JR, Buzy JM, Zink MC, Clements JE (1992).Expression directed from HIV long terminal repeats inthe central nervous system of transgenic mice. Science258: 1804 ± 1808.

Cunningham ET, De Zouza EB (1993). Interleukin-1receptors in the brain and endocrine tissues. ImmunolToday 14: 171 ± 176.

D'Souza MP, Harden VA (1996). Chemokines and HIV-1second receptors Con¯uence of two ®elds generatesoptimism in AIDS research. Nature Med 2: 1293 ±1300.

Davis CB, Dikic I, Unutmaz D, Hill CM, ArthosJ, SianiMA, Thompson DA, Schlessinger J, Littman DR(1997). Signal Transduction Due to HIV-1 EnvelopeInteractions with Chemokine Receptors CXCR4 orCCR5. J Exp Med 186: 1793 ± 1798.

Deng HK, Liu R, Ellmeier W, Choe S, Unutmaz D,Burkhart M, Di Marzio P, Marmon S, Sutton RE, HillCM, Davis CB, Peiper SC, Schall TJ, Littman DR,Landau NR (1996). Identi®cation of a major co-receptor for primary isolates of HIV-1. Nature 381:661 ± 666.

Deng HK, Unutmaz D, KewalRamani VN, Littman DR(1997). Expression cloning of new receptors used bysimian and human immunode®ciency viruses. Nature388: 296 ± 300.

Desbaillets I, Diserens AC, Tribolet N, Hamou MF, MeirEGV (1997). Upregulation of Interleukin 8 by Oxygen-deprived Cells in Glioblastoma Suggests a Role inLeukocyte Activation, Chemotaxis, and Angiogenesis.J Exp Med 186: 1201 ± 1212.

Desbaillets I, Tada M, de Tribolet N, Diserens AC,Hamou MF, Van Meir EG (1994). Human astrocytomasand glioblastomas express monocyte chemoattractantprotein-1 (MCP-1) in vivo and in vitro. InternationalJournal of Cancer, 58: 240 ± 247.

Dohlman HG, Thorner J, Caron MG, Lefkowitz RJ (1991).Model systems for the study of seven transmembrane-segment receptors. Annu Rev Biochem 60: 653 ± 688.

Doranz BJ, Rucker J, Yi YJ, Smyth RJ, Samson M, PeiperSC, Parmentier M, Collman RG, Doms RW (1996). Adual-tropic primary HIV-1 isolate that used fusin andthe b-chemokine receptors CKR-5, CKR-3, and CKR-2bas fusion cofactors. Cell, 85: 1149 ± 1158.

Dragic T, Charneau P, Clavel F, Alizon M. (1992).Complementation of murine cells for human immu-node®ciency virus envelope/CD4-mediated fusion inhuman/murine heterokaryons. J Virol 66: 4794 ± 4802.

Dragic T, Litwin V, Allaway GP, Martin SR, Huang YX,Nagashima KA, Cayanan C, Maddon PJ, Koup RA,Moore JP, Paxton WA (1996). HIV-1 entry into CD4+

cells is mediated by the chemokine receptor CC-CKR-5. Nature 381: 667 ± 673.

Ebers GC (1986). Multiple sclerosis and other demyeli-nating disease. In: Diseases of the nervous system.Asbury AK, McKhann GM, McDonald WI (eds).Ardmore medical books: Philadelphia, pp 1268 ± 1281.

Edinger AL, Amedee A, Miller K, Doranz BJ, Endres M,Sharron M, Samson M, Lu Z, Clements JE, Murphey-Corb M, Peiper SC, Parmentier M, Broder CC, DomsRW (1997a). Differential utilization of CCR5 bymacrophage and T cell tropic simian immunode®-ciency virus strains. Proc Natl Acad Sci USA 94:4005 ± 4010.

Edinger AL, Mankowski JL, Doranz BJ, Margulies BJ, LeeB, Rucker J, Sharron M, Hoffman TL, Berson JF, ZinkMC, Hirsch VM, Clements JE, Doms RW (1997b). CD4-independent, CCR5-dependent infection of braincapillary endothelial cells by a neurovirulent simianimmunode®ciency virus strain. Proc Natl Acad SciUSA 94: 14742 ± 14747.

Endres MJ, Clapham PR, Marsh M, Ahuja M, Turner JD,McKnight A, Thomas JF, Stoebenau-Haggarty B, ChoeS, Vance PJ, Wells TNC, Power CA, Sutterwala SS,Doms RW, Landau NR, Hoxie JA (1996). CD4-independent infection by HIV-2 is mediated byFusin/CXCR4. Cell 87: 745 ± 756.

Farzan M, Choe H, Martin K, Marcon L, Hofmann W,Karlsson G, Sun Y, Barrett P, Marchand N, SullivanN, Gerard N, Gerard C, Sodroski J (1997). Two OrphanSeven-Transmembrane Segment Receptors Which AreExpressed in CD4-positive Cells Support SimianImmunode®ciency Virus Infection. J Exp Med 186:405 ± 411.

Feng Y, Broder CC, Kennedy PE, Berger EA (1996). HIV-1 entry cofactor : Functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science272: 872 ± 877.

Garcia-Zepeda EA, Combadiere C, Rothenberg ME, Sara®MN, Lavigne F, Hamid Q, Murphy PM, Luster AD(1996). Human monocyte chemoattractant protein(MCP)-4 is a novel CC chemokine with activities onmonocytes, eosinophils, and basophils induced inallergic and nonallergic in¯ammation that signalsthrough the CC chemokine receptors (CCR)-2 and -3.J Immunol 157: 5613 ± 5626.

Gelbard HA, James HJ, Sharer LR, Perry SW, Saito Y,Kazee AM, Blumberg BM, Epstein LG (1995).Apoptotic neurons in brains from paediatric patientswith HIV-1 encephalitis and progressive encephalo-pathy. Neuropathology & Applied Neurobiology 21:208 ± 217.

Ghorpade A, Xia MQ, Hyman BT, Bersidsky Y, NukunaA, Bock P, Che MH, Limoges J, Gendelman HE,Mackay CR (1998). Role of the b-chemokine receptorsCCR3 and CCR5 in human immunode®ciency virustype 1 infection of monocytes and microglia. J Virol72: 3351 ± 3361.

Gitter BD, Cox LM, Rydel RE, May PC (1995). Amyloid bpeptide potentiates cytokine secretion by interleukin-1b-activated human astrocytoma cells. Proc Natl AcadSci USA 92: 10738 ± 10741.

Glabinski AR, Tani M, Strieter RM, Tuohy VK, RansohoffRM (1997). Synchronous synthesis of a- and b-chemokines by cells of diverse lineage in the centralnervous system of mice with relapses of chronicexperimental autoimmune encephalomyelitis. Am JPathol 150: 617 ± 630.


23

Glushakova S, Baibakov B, Zimmerberg J, Margolis LB(1997). Experimental HIV infection of human lym-phoid tissue: correlation of CD4+ T cell depletionand virus syncytium-inducing/non-syncytium-indu-cing phenotype in histocultures inoculated withlaboratory strains and patient isolates of HIV type 1.AIDS Res Hum Retroviruses 13: 461 ± 471.

Godiska R, Chantry D, Dietsch GN, Gray PW (1995).Chemokine expression in murine experimental aller-gic encephalomyelitis. J Neuroimmunology 58: 167 ±176.

Gupta SK, Lysko PG, Pillarisetti K, Ohlstein E, Stadel JM(1998). Chemokine Receptors in Human EndothelialCells. Functional expression of CXCR4 and itstranscriptional regulation by in¯ammatory cytokines.J Biol Chem 273: 4282 ± 4287.

Hadley TJ, Lu Z-h, Wasniowska K, Martin AW, PeiperSC, Hesselgesser J, Horuk R (1994). Post-CapillaryVenule Endothelial Cells in Kidney Express a Multi-speci®c Chemokine Receptor that is Structurally andFunctionally Identical to the Erythroid Isoform, whichis the Duffy Blood Group Antigen. J Clin Invest 94:985 ± 991.

He JL, Chen YZ, Farzan M, Choe HY, Ohagen A, GartnerS, Busciglio J, Yang XY, Hofmann W, Newman W,Mackay CR, Sodroski J, Gabuzda D (1997). CCR3 andCCR5 are co-receptors for HIV-1 infection of micro-glia. Nature 385, 645 ± 649.

Hesselgesser J, Halks-Miller M, DelVecchio V, Peiper SC,Hoxie J, Kolson DL, Taub D, Horuk R (1997). CD4-independent association between HIV-1 gp120 andCXCR4: Functional chemokine receptors are ex-pressed in human neurons. Curr Biol 7, 112 ± 121.

Hesselgesser J, Taub D, Baskar P, Greenberg M, Hoxie J,Kolson DL, Horuk R (1998). Neuronal apoptosisinduced by HIV-1 gp120 and the chemokine SDF-1ais mediated by the chemokine receptor CXCR4.Current Biology 8: 595 ± 598.

Hirka G, Prakash K, Kawashima H, Plotkin SA, AndrewsPW, Gonczol E (1991). Differentiation of humanembryonal carcinoma cells induces human immuno-de®ciency virus permissiveness which is stimulatedby human cytomegalovirus coinfection. J Virol 65:2732 ± 2735.

Honma K, Parker KC, Becker KG, McFarland HF, ColiganJE, Biddison WE (1997). Identi®cation of an epitopederived from human proteolipid protein that caninduce autoreactive CD8+ cytotoxic T lymphocytesrestricted by HLA-A3: evidence for cross-reactivitywith an environmental microorganism. J Neuroimmu-nol 73: 7 ± 14.

Horuk R (1994). Molecular properties of the chemokinereceptor family. Trends Pharmacol Sci 15: 159 ± 165.

Horuk R, Chitnis CE, Darbonne WC, Colby TJ, Rybicki A,Hadley TJ, Miller LH (1993). A receptor for themalarial parasite Plasmodium vivax: The erythrocytechemokine receptor. Science 261: 1182 ± 1184.

Horuk R, Hesselgesser J, Zhou Y, Faulds D, Halks-MillerM, Taub D, Samson M, Parmentier M, Rucker J,Doranz BJ, Doms RW (1998). The CC chemokine I-309inhibits CCR8-dependent infection by diverse HIV-1strains. J Biol Chem 273: 386 ± 391.

Horuk R, Martin AW, Wang Z-X, Scweitzer L, Gerassi-mides A, Lu Z-H, Hesselgesser J, Kim J, Parker J,Hadley TJ, Perez HD, Peiper SC (1997). Expression ofchemokine receptors by subsets of neurons in thenormal central nervous system. J Immunol 158:2882 ± 2890.

Hosie MJ, Broere N, Hesselgesser J, Turner JD, Hoxie JA,Neil JC, Willett BJ (1998). Modulation of felineimmunode®ciency virus infection by stromal cell-derived factor. J Virol 72: 2097 ± 2104.

Huber AR, Kunkel SL, Todd RF, Weiss SJ (1991).Regulation of transendothelial neutrophil migrationby endogenous interleukin-8. Science 254: 99 ± 102.

Hulkower K, Brosnan CF, Aquino DA, Cammer W,Kulshrestha S, Guida MP, Rapoport DA, Berman JW(1993). Expression of CSF-1, c-fms and MCP-1 in thecentral nervous system of rats with experimentalallergic encephalomyelitis. J Immunol 150: 2525 ±2533.

Imai T, Hieshima K, Haskell C, Baba M, Nagira M,Nishimura M, Kakizaki M, Takagi S, Nomiyama H,Schall TJ, Yoshie O (1997). Identi®cation and mole-cular characterization of fractalkine receptor CX3CR1,which mediates both leukocyte migration and adhe-sion. Cell 91: 521 ± 530.

Jinno A, Shimizu N, Soda Y, Haraguchi Y, Kitamura T,Hoshino H (1998). Identi®cation of the chemokinereceptor TER1/CCR8 expressed in brain-derived cellsand T cells as a new coreceptor for HIV-1 infection.Biochem Biophys Res Commun 243: 497 ± 502.

Karpus WJ, Kennedy KJ (1997). MIP-1alpha and MCP-1differentially regulate acute and relapsing autoim-mune encephalomyelitis as well as Th1/Th2 lympho-cyte differentiation. J Leukoc Biol 62: 681 ± 687.

Kleppner SR, Robinson KA, Trojanowski JQ, Lee VM(1995). Transplanted human neurons derived from ateratocarcinoma cell line (NTera-2) mature, integrate,and survive for over 1 year in the nude mouse brain. JComp Neurol 357: 618 ± 632.

Kolson D, Pomerantz D (1996). AIDS Dementia and HIV-1-Induced Neurotoxicity: Possible Pathogenic Associa-tions and Mechanisms. Journal of Biomedical Science3: 389 ± 414.

Kuchroo VK, Martin CA, Greer JM, Ju ST, Sobel RA, DorfME (1993). Cytokines and adhesion molecules con-tribute to the ability of myelin proteolipid protein-speci®c T cell clones to mediate experimental allergicencephalomyelitis. J Immunol 151: 4371 ± 4382.

Lane TE, Asensio VC, Yu NC, Paoletti AD, Campbell IL,Buchmeier MJ (1998). Dynamic regulation of a- and b-chemokine expression in the central nervous systemduring mouse hepatitis virus-induced demyelinatingdisease. J Immunol 160: 970 ± 978.

Lavi E, Strizki JM, Ulrich AM, Zhang W, Fu L, Wang Q,O'Connor M, Hoxie JA, Gonzalez-Scarano F (1997).CXCR-4 (Fusin), a co-receptor for the type 1 humanimmunode®ciency virus (HIV-1), is expressed in thehuman brain in a variety of cell types, includingmicroglia and neurons. Am J Pathol 151: 1035 ± 1042.


24

Li YS, Shyy YJ, Wright JG, Valente AJ, Cornhill JF,Kolattukudy PE (1993). The expression of monocytechemotactic protein (MCP-1) in human vascularendothelium in vitro and in vivo. Molecular &Cellular Biochemistry 126: 61 ± 68.

Lipton SA, Sucher NJ, Kaiser PK, Dreyer EB (1991).Synergistic effects of HIV coat protein and NMDAreceptor-mediated neurotoxicity. Neuron 7: 111 ± 118.

Luster AD (1998). Chemokines chemotactic cytokinesthat mediate in¯ammation. N Engl J Med 338: 436 ±445.

Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T,Kishimoto T, Bronson RT, Springer TA (1998).Impaired B-lymphopoiesis, myelopoiesis, and derailedcerebellar neuron migration in CXCR4- and SDF-1de®cient mice. Proc Natl Acad Sci USA 95: 9448 ±9453.

Marcon L, Choe H, Martin KA, Farzan M, Ponath PD,Wu LJ, Newman W, Gerard N, Gerard C, Sodroski J(1997). Utilization of C-C chemokine receptor 5 by theenvelope glycoproteins of a pathogenic simian im-munode®ciency virus, SIVmac239. J Virol 71: 2522 ±2527.

Marfaing-Koka A, Devergne O, Gorgone G, Portier A,Schall TJ, Galanaud P, Emilie D (1995). Regulation ofthe production of the RANTES chemokine byendothelial cells: Synergistic induction by IFN-gammaplus TNF-a and inhibition by IL-4 and IL-13. JImmunol 154: 1870 ± 1878.

McManus CM, Brosnan CF, Berman JW (1998). Cytokineinduction of MIP-1alpha and MIP-1beta in humanfetal microglia. J Immunol 160: 1449 ± 1455.

Merrill JE (1987). Macroglia : neural cells responsive tolymphokines and growth factors. Immunology Today8, 146 ± 150.

Meucci O, Miller RJ (1996). gp120-induced neurotoxicityin hippocampal pyramidal neuron cultures: protectiveaction of TGF-beta1. Journal of Neuroscience 16:4080 ± 4088.

Miyagishi R, Kikuchi S, Takayama C, Inoue Y, Tashiro K(1997). Identi®cation of cell types producing RANTES,MIP-1 alpha and MIP-1 beta in rat experimentalautoimmune encephalomyelitis by in situ hybridiza-tion. J Neuroimmunol 77: 17 ± 26.

Moses AV, Williams SE, Strussenberg JG, Heneveld ML,Ruhl RA, Bakke AC, Bagby GC, Nelson JA (1997).HIV-1 induction of CD40 on endothelial cellspromotes the outgrowth of AIDS-associated B-celllymphomas. Nature Medicine 3: 1242 ± 1249.

Murakami K, Ueno A, Yamanouchi K, Kondo T (1995).Thrombin induces GRO alpha/MGSA production inhuman umbilical vein endothelial cells. ThrombosisResearch 79: 387 ± 394.

Neote K, DiGregorio D, Mak JY, Horuk R, Schall TJ(1993). Molecular cloning, functional expression, andsignaling characteristics of a C-C chemokine receptor.Cell 72: 415 ± 425.

Pan Y, Lloyd C, Zhou H, Dolich S, Deeds J, Gonzalo JA,Vath J, Gosselin M, Ma J, Dussault B, Woolf E,Alperin G, Culpepper J, Gutierrez-Ramos JC, GearingD (1997). Neurotactin, a membrane-anchored chemo-kine upregulated in brain in¯ammation. Nature 387:611 ± 617.

Peiper S, Wang Z-x, Neote K, Martin AW, Showell HJ,Conklyn MJ, Ogborne K, Hadley TJ, Zhao-hai L,Hesselgesser J, Horuk R (1995). The Duffy antigen/receptor for chemokines (DARC) is expressed inendothelial cells of Duffy negative individuals wholack the erythrocyte receptor. J Exp Med 181: 1311 ±1317.

Piali L, Weber C, LaRosa G, Mackay CR, Springer TA,Clark-Lewis I, Moser B (1998). The chemokinereceptor CXCR3 mediates rapid and shear-resistantadhesion-induction of effector T lymphocytes by thechemokines IP10 and Mig. Eur J Immunol 28: 961 ±972.

Ransohoff RM, Hamiltion TA, Tani M, Stoler MH, ShickHE, Major JA, Estes ML, Thomas DM, Tuohy VK(1993). Astrocyte expression of mRNA encodingcytokines IP-10 and JE/MCP-1 in experimental auto-immune encephalomyelitis. FASEB J 7: 592 ± 600.

Reeves JD, McKnight A, Potempa S, Simmons G, GrayPW, Power CA, Wells T, Weiss RA, Talbot SJ (1997).CD4-independent infection by HIV-2 (ROD/B): Use ofthe 7-transmembrane receptors CXCR-4, CCR-3, andV28 for entry. Virology 231: 130 ± 134.

Rollins BJ, Pober JS (1991). Interleukin-4 induces thesynthesis and secretion of MCP-1/JE by humanendothelial cells. Am J Pathol 138: 1315 ± 1319.

Roos RS, Loetscher M, Legler DF, Clark-Lewis I,Baggiolini M, Moser B (1997). Identi®cation ofCCR8, the receptor for the human CC chemokine I-309. J Biol Chem 272: 17251 ± 17254.

Rottman JB, Ganley KP, Williams K, Wu LJ, Mackay CR,Ringler DJ (1997). Cellular localization of the chemo-kine receptor CCR5 ± Correlation to cellular targets ofHIV-1 infection. Am J Pathol 151: 1341 ± 1351.

Rucker J, Edinger AL, Sharron M, Samson M, Lee B,Berson JF, Yi Y, Margulies B, Collman RG, Doranz BJ,Parmentier M, Doms RW (1997). Utilization ofchemokine receptors, orphan receptors, and herpes-virus-encoded receptors by diverse human and simianimmunode®ciency viruses. J Virol 71: 8999 ± 9007.

Samson M, Labbe O, Mollereau C, Vassart G, ParmentierM (1996). Molecular cloning and functional expres-sion of a new human CC-chemokine receptor gene.Biochemistry 35: 3362 ± 3367.

Sasseville VG, Smith MM, Mackay CR, Pauley DR,Mans®eld KG, Ringler DJ, Lackner AA (1996).Chemokine expression in simian immunode®ciencyvirus-induced AIDS encephalitis. Am J Pathol 149:1459 ± 1467.

Scarlatti G, Tresoldi E, BjoÈ rndal AÊ , Fredriksson R,Colognesi C, Deng HK, Malnati MS, Plebani A,Siccardi AG, Littman DR, Fenyo EM, Lusso P (1997).In vivo evolution of HIV-1 co-receptor usage andsensitivity to chemokine-mediated suppression. Nat-ure Med 3: 1259 ± 1265.

Schall T 1994. The Chemokines. In: The CytokineHandbook. Thompson A. Academic Press: San Diego,pp 419 ± 460.


25

Schmidtmayerova H, Nottet HSLM, Nuovo G, Raabe T,Flanagan CR, Dubrovsky L, Gendelman HE, Cerami A,Bukrinsky M, Sherry B (1996). Human immunode®-ciency virus type 1 infection alters chemokine bpeptide expression in human mnocytes: Implicationsfor recruitment of leukocytes into brain and lymphnodes. Proc Natl Acad Sci USA 93: 700 ± 704.

Shieh JT, Albright AV, Sharron M, Gartner S, Strizki J,Doms RW, Gonzalez-Scarano F (1998). Chemokinereceptor utilization by human immunode®ciencyvirus type 1 isolates that replicate in microglia. JVirol 72: 4243 ± 4249.

Springer TA (1994). Traf®c signals for lymphocyterecirculation and leukocyte emigration: the multistepparadigm. Cell 76: 301 ± 314.

Strieter RM, Kunkel SL, Showell HJ, Rennick DJ, PhanSH, Ward RA, Marks RM (1989). Endothelial cell geneexpression of a neutrophil chemotactic factor by TNF-a, LPS, and IL-1b. Science 243: 1467 ± 1469.

Takeshima H, Kuratsu J, Takeya M, Yoshimura T, UshioY (1994). Expression and localization of messengerRNA and protein for monocyte chemoattractantprotein-1 in human malignant glioma. Journal ofNeurosurgery 80: 1056 ± 1062.

Tanabe S, Heesen M, Berman MA, Fischer MB,YoshizawaI, Luo Y, Dorf ME (1997a). Murine astro-yctes express a functional chemokine receptor. JNeurosci 17: 6522 ± 6528.

Tanabe S, Heesen M, Yoshizawa I,Berman MA, Luo Y,Bleul CC, Springer TA, Okuda K, Gerard N, Dorf ME(1997b). Functional expression of the CXC-chemokinereceptor-4/fusin on mouse microglial cells and astro-cytes. J Immunol 159: 905 ± 911.

Tani M, Fuentes ME, Peterson JW, Trapp BD, DurhamSK, Loy JK, Bravo R, Ransohoff RM, Lira SA (1996a).Neutrophil, in®ltration, glial reaction, and neurologi-cal disease in transgenic mice expressing the chemo-kine N51/KC in oligodendrocytes. J Clin Invest 98:529 ± 539.

Tani M, Glabinski AR, Tuohy VK, Stoler MH, Estes ML,Ransohoff RM (1996b). In situ hybridization analysisof glial ®brillary acidic protein mRNA revealsevidence of biphasic astrocyte activation during acuteexperimental autoimmune encephalomyelitis. Am JPathol 148 889 ± 896.

Tiffany HL, Lautens LL, Gao JL, Pease J, Locati M,Combadiere C, Modi W, Bonner TI, Murphy PM(1997). Identi®cation of CCR8: A human monocyteand thymus receptor for the CC chemokine I-309. JExp Med 186: 165 ± 170.

Toggas SM, Masliah E, Rockenstein EM, Rall GF,Abraham CR, Mucke L (1994). Central nervous systemdamage produced by expression of the HIV-1 coatprotein gp120 in transgenic mice. Nature 367: 188 ±193.

Vallat AV, De Girolami U, He JL, Mhashilkar A, MarascoW, Shi B, Gray F, Bell J, Keohane C, Smith TW,Gabuzda D (1998). Localization of HIV-1 co-receptorsCCR5 and CXCR4 in the brain of children with AIDS.Am J Pathol 152: 167 ± 178.

Van Snick J, Houssiau F, Proost P, Van Damme J,Renauld JC (1996). I-309/T cell activation gene-3chemokine protects murine T cell lymphomas againstdexamethasone-induced apoptosis. J Immunol 157:2570 ± 2576.

Volin MV, Joseph E, Shockley MS, Davies PF (1998).Chemokine receptor CXCR4 expression in endothe-lium. Biochem Biophys Res Commun 242: 46 ± 53.

Weissman D, Rabin RL, Arthos J, Rubbert A, Dybul M,Swofford R, Venkatesan S, Farber JM, Fauci AS(1997). Macrophage-tropic HIV and SIV envelopeproteins induce a signal through the CCR5 chemokinereceptor. Nature 389: 981 ± 985.

Westmoreland SV, Rottman JB, Williams KC, LacknerAA, Sasseville VG (1998). Chemokine receptor ex-pression on resident and in¯ammatory cells in thebrain of macaques with simian immunode®ciencyvirus encephalitis. Am J Pathol 152: 659 ± 665.

Willett BJ, Hosie MJ, Neil JC, Turner JD, Hoxie JA(1997a). Common mechanism of infection by lenti-viruses. Nature 385: 587 ± 587.

Willett BJ, Picard L, Hosie MJ, Turner JD, Adema K,Clapham PR (1997b). Shared usage of the chemokinereceptor CXCR4 by the feline and human immunode-®ciency viruses. J Virol 71: 6407 ± 6415.

Xia M, Qin S, McNamara M, Mackay C, Hyman BT(1997). Interleukin-8 receptor B immunoreactivity inbrain and neuritic plaques of Alzheimer's disease. AmJ Path 150: 1267 ± 1274.

Zhang L, He T, Talal A, Wang G, Frankel SS, Ho DD(1998). In vivo distribution of the human immunode-®ciency Virus/Simian immunode®ciency virus core-ceptors: CXCR4, CCR3, and CCR5. J Virol 72: 5035 ±5045.

Zou Y-R, Kottman AH, Koruda M, Taniuchi I, LittmanDR (1998). Function of the chemokine receptorCXCR4 in haematopoiesis and in cerebellar develop-ment. Nature 393, 595 ± 599.


26

Documents

Chemokine and chemokine receptor expression in the central ...1)/13-26.pdf · Chemokine and chemokine receptor expression in the central nervous system Joseph Hesselgesser*,1 and