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Accueil > Agenda > Les séminaires Jean Roche > CRMP2, un nouvel acteur de la mobilité lymphocytaire.

CRMP2, un nouvel acteur de la mobilité lymphocytaire.

Lundi 28 novembre 2005,11h, salle Lissitzky.

Bibliographie

1 : *Neuromolecular Med. 2005 ;7(3):207-16.

*T-cells in neuronal injury and repair : semaphorins and related T-cell signals.*

*Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Vincent P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Vuaillat C* <http://www.ncbi.nlm.nih.gov/entrez/...> .

U433 Inserm, Neurobiologie Experimentale et Physiopathologie, Faculte de Medecine Laennec Rue Guillaume Paradin, 69372 Lyon Cedex 08, France.

There are many parallels between the hematopoietic and the nervous systems in terms of mechanisms regulating their development and functions. In neuroinflammatory diseases, interaction between the immune and nervous systems through shared molecules is suspected to trigger an inappropriate crosstalk and lead to demyelination and axonal loss. Here we focus on semaphorins and their functions in the nervous and immune systems and point out the deleterious effect of an immune semaphorin, semaphorin 4D (Sema4D)/CD100, on oligodendrocyte integrity and survival. We propose immune semaphorins as new candidates involved in the pathogenic mechanisms of neuroinflammatory diseases, promoting demyelination, and impairing neuroregeneration.


*2 : *J Neurochem. 2005 Sep ;94(6):1580-93. Epub 2005 Jul 18.

Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> *Impairment of blood-cerebrospinal fluid barrier properties by retrovirus-activated T lymphocytes : reduction in cerebrospinal fluid-to-blood efflux of prostaglandin E2.*

*Khuth ST* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Strazielle N* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Belin MF* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Ghersi-Egea JF* <http://www.ncbi.nlm.nih.gov/entrez/...> .

INSERM U433, Universite Claude Bernard Lyon 1, Faculte de Medecine RTH Laennec, Lyon, France.

The choroid plexus epithelium forms the interface between the blood and the CSF. In conjunction with the tight junctions restricting the paracellular pathway, polarized specific transport systems in the choroidal epithelium allow a fine regulation of CSF-borne biologically active mediators. The highly vascularized stroma delimited by the choroidal epithelium can be a reservoir for retrovirus-infected or activated immune cells. In this work, new insight in the implication of the blood-CSF barrier in neuroinfectious and inflammatory diseases is provided by using a differentiated cellular model of the choroidal epithelium, exposed to infected T lymphocytes. We demonstrate that T cells activated by a retroviral infection, but not non-infected cells, reduce the transporter-mediated CSF-to-blood efflux of organic anions, in particular that of the potent pro-inflammatory prostaglandin PGE2, via the release of soluble factors. A moderate alteration of the paracellular permeability also occurs. We identified the viral protein Tax, oxygenated free radicals, matrix-metalloproteinases and pro-inflammatory cytokines as active molecules released during the exposure of the epithelium to infected T cells. Among them, tumour necrosis factor and interleukin 1 are directly involved in the mechanism underlying the decrease in some choroidal organic anion efflux. Given the strong involvement of CSF-borne PGE2 in sickness behaviour syndrome, these data suggest that the blood-CSF barrier plays an important role in the pathophysiology of neuroinflammation and neuroinfection, via changes in the transport processes controlling the CSF biodisposition of PGE2.


*3 : *Virus Genes. 2005 Jan ;30(1):103-12.

Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> *Cumulative mutations in the genome of Echovirus 6 during establishment of a chronic infection in precursors of glial cells.*

*Beaulieux F* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Zreik Y* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Deleage C* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Sauvinet V* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Legay V* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Kean KM* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Lina B* <http://www.ncbi.nlm.nih.gov/entrez/...> .

Laboratoire de Virologie, UMR CNRS 5537, Domaine Rockefeller, F-69373, Lyon cedex 08, France.

Although Enteroviruses are mainly described as responsible for acute diseases, their role in severe chronic pathology has been also established. Echovirus 6-like sequences have been detected by PCR analysis in central nervous system specimens from patients presenting with Amyotrophic Lateral Sclerosis. These findings suggested a persistent infection with viruses that underwent, genetic changes precluding viral particle release. To support this hypothesis, we developed a model system of Echovirus 6 chronic infection in precursors of glial cells. The nucleotide sequences of the 5’non-translated region (5’NTR), 2A and 3C regions of the virus developing persistent genome were analysed during establishment of the chronic phenotype. This study revealed that at day 160 of chronic infection, several mutations were observed : one mutation at nucleotide 108 upstream the domain II of the internal ribosome entry site (IRES) structure, one mutation at nucleotide 30 in the cloverleaf, and two mutations in the 2A region (translated in His48 to Tyr, and Ile 123 to Met). No mutations were detected in the 3C region. The impact of these mutations on viral replication have been analysed in a rabbit reticulocyte lysate (RRL) translation assay supplemented with HeLa cell lysate, and by plaque assay. Viruses with these mutations displayed a phenotype with a significant reduction of replication, while in vitro translation was not affected by the nucleotide 108 mutation. This model allowed the description of molecular changes observed in the genome of Echovirus 6 during the establishment of a chronic infection phenotype, and may be helpful for the understanding of the mechanisms leading Enteroviruses to develop chronic infections in man.


*4 : *Scand J Clin Lab Invest. 2004 Apr ;64(2):101-7.

*Extracellular matrix protein expression in cerebrospinal fluid from patients with tropical spastic paraparesis associated with HTLV-I and Creutzfeldt-Jakob disease.*

*Cartier L* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Garcia L* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Kettlun AM* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Castaneda P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Collados L* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Vasquez F* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Belin MF* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Valenzuela MA* <http://www.ncbi.nlm.nih.gov/entrez/...> .

Departamento de Ciencias Neurologicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.

The cerebrospinal fluid (CSF) is in direct contact with the extracellular space of the CNS, thus biochemical processes in the CNS could potentially be reflected in the CSF. Changes in extracellular matrix (ECM) proteins can be studied through their analysis in the CSF. ECM plays an essential role in CNS homeostasis and several proteins such as laminin (LN), fibronectin (FN), thrombospondin (TS) and heparan sulphate proteoglycan (HS, perlecan) form part of its structure. Possible changes in the levels of these proteins were investigated in two different pathologies—tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) (n=25) and Creutzfeldt-Jakob disease (CJD) (n=19)—and compared with those in a control group with or without neurological disease (n=25). CSF analyses were carried out using monoclonal or monospecific polyclonal antibodies. In comparison with the control group, it was found that TSP/HAM patients presented significantly higher levels of LN, TS and HS, while in CJD patients the levels of FN, TS and HS were increased. In CJD patients the HS level was almost double that of the TSP/HAM patients. These results suggest a distinct pattern of ECM proteins in CSF in relation to the type of neurological disease. TSP/HAM is a chronic motor disease that affects the white matter of the spinal cord, while CJD is a subacute dementia that affects cerebral neurons and their synapsis.


*5 : *J Immunol. 2004 Jan 15 ;172(2):1246-55.

Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> *Semaphorin CD100 from activated T lymphocytes induces process extension collapse in oligodendrocytes and death of immature neural cells.*

*Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Vincent P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Vuaillat C* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Verlaeten O* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Cartier L* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Marie-Cardine A* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Mutin M* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Bensussan A* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Belin MF* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Boumsell L* <http://www.ncbi.nlm.nih.gov/entrez/...> .

INSERM Unit 433, Experimental Neurobiology and Physiopathology, Federative Institut of Neuroscience 19, Faculty of Medicine R Laennec, rue G. Paradin, 69372 Lyon CEDEX 08, France. giraudon lyon.inserm.fr

An inappropriate cross talk between activated T lymphocytes infiltrating the CNS and neural cells can sustain the onset and progression of demyelination and axonal degeneration in neuroinflammatory diseases. To mimic this deleterious cross talk, we designed an experimental paradigm consisting of transient cocultures of T lymphocytes chronically activated by retrovirus infection (not virus productive) with human multipotent neural precursors or primary oligodendrocytes from rat brain. We showed that activated T lymphocytes induced apoptotic death of multipotent neural progenitors and immature oligodendrocytes after a progressive collapse of their process extensions. These effects were reminiscent of those induced by brain semaphorin on neural cells. Blockade by specific Abs of soluble CD100 (sCD100)/semaphorin 4D released by activated T cells, or treatment with rsCD100, demonstrated that this immune semaphorin has the ability to collapse oligodendrocyte process extensions and to trigger neural cell apoptosis, most likely through receptors of the plexin family. The specific presence of sCD100 in the cerebrospinal fluid and of CD100-expressing T lymphocytes in the spinal cord of patients suffering with neuroinflammatory demyelination pointed to the potential pathological effect of sCD100 in the CNS. Thus, our results show that CD100 is a new important element in the deleterious T cell-neural cell cross talk during neuroinflammation and suggest its role in demyelination or absence of remyelination in neuroinflammatory diseases including multiple sclerosis and human T lymphotropic virus type 1-associated myelopathy.


*6 : *J Neuropathol Exp Neurol. 2003 Dec ;62(12):1254-64.

Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> *Pro-inflammatory cytokines modulate matrix metalloproteinase secretion and organic anion transport at the blood-cerebrospinal fluid barrier.*

*Strazielle N* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Khuth ST* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Murat A* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Chalon A* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Belin MF* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Ghersi-Egea JF* <http://www.ncbi.nlm.nih.gov/entrez/...> .

Unite INSERM 433, Faculte de Medecine Laennec, Lyon, France.

Neuroinflammation and neuroinfection trigger cytokine-mediated responses that include an increase in the cerebrospinal fluid (CSF) levels of pro-inflammatory matrix metalloproteinases (MMPs) and organic anions such as leukotrienes and prostaglandins. The choroid plexus (CP) epithelium forming the interface between the blood and the CSF regulates the CSF concentration of bioactive organic anions and is involved in neuro-immune regulation. We demonstrated that both fourth and lateral ventricle CPs are a source of pro- and active MMP-2 and MMP-9 in the brain. Using a cellular model of the blood-CSF barrier, we showed that a pro-inflammatory cytokine treatment leads to an increase in the choroidal MMP secretion at either the apical or the basolateral membrane, depending on the ventricular origin of the choroidal cells. This effect was not concomitant with an alteration in the structural blood-CSF barrier. Neither was the pool of antioxidant sulfhydryls in the choroidal cells challenged. In contrast, the efficiency of the choroidal epithelium to clear the CSF from organic anions was highly reduced. Thus, during inflammation, the CPs could be one source of MMPs found in the CSF facilitate leucocyte migration by secreting MMPs into the choroidal stroma, and promote the inflammatory process by failing in its ability to clear deleterious compounds from the brain.


*7 : *J Soc Biol. 2003 ;197(2):103-12.

*[Astrocytes, cells involved in neuro-immune interactions in the central nervous system]*

[Article in French]

*Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Malcus C* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Chalon A* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Vincent P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Khuth S* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Bernard A* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Belin MF* <http://www.ncbi.nlm.nih.gov/entrez/...> .

Inserm U433 Faculte de Medecine R Laennec, 69372 Lyon. giraudon lyon.inserm.fr

The astrocyte, the major glial cell in the central nervous system, may influence many aspects of inflammation and immune reactivity within the brain. We have established a model of chronically activated T lymphocytes, interacting with neural cells of diverse origin to study the complex immune regulatory system suspected to lead to neuroinflammatory diseases. We show that human astrocytes became reactive following T cell contact, secreting proinflammatory cytokines, matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinase (TIMP). The altered MMP/TIMP system was shown to be involved in deleterious effects displayed by activated T cells towards human multipotent neural precursers by controlling their sensitivity to T cell-induced Fas-mediated apoptosis. MMP/TIMP was suspected to stabilize Fas at the cell membrane. In a model of mixed rat glial cells in primary culture (astrocytes, oligodendrocytes), activated T lymphocytes induced the collapse of processes and the death of immature oligodendrocytes. These effects were associated with upregulation of Fas at the cell surface of oligodendrocytes and secretion of MMP and TIMP by astrocytes. By amplifying the expression of inflammatory molecules including the MMP/TIMP system, astrocytes appear to be a crucial relay in the deleterious molecular cascade triggered by activated T lymphocytes. Detection of altered MMP/TIMP in patients suffering from myelopathy associated with retroviral infection (HTLV-1) strongly suggests its involvement in the physiopathological process of the disease.


*8 : *Eur J Neurosci. 2003 May ;17(9):1820-8.

Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> *Impaired glutamate uptake and EAAT2 downregulation in an enterovirus chronically infected human glial cell line.*

*Legay V* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Deleage C* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Beaulieux F* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Aymard M* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Lina B* <http://www.ncbi.nlm.nih.gov/entrez/...> .

UMR 5537, Laboratoire de Virologie Medicale, Domaine Rockefeller, Lyon, France.

Rapid and efficient uptake of glutamate via the high-affinity glutamate transporter EAAT2 is important for limiting glutamate-mediated excitotoxicity involved in neuronal death. Furthermore, there is evidence of altered glutamate uptake and catabolism in motor neuron diseases. Such a defect has been reported in amyotrophic lateral sclerosis, the major motor neuron disease, and was associated with impairment in EAAT2 processing. We recently reported the presence of enterovirus genome specifically in the anterior horn of amyotrophic lateral sclerosis cases, suggesting the involvement of a chronic/persistent enterovirus infection in amyotrophic lateral sclerosis. To investigate a putative link between enterovirus infection and the glutamate-mediated excitotoxicity observed in amyotrophic lateral sclerosis, we developed an in vitro model consisting of a human glial cell line infected with ECHOvirus 6, one of the enteroviruses with sequences closely related to those detected in patients with amyotrophic lateral sclerosis. In these glial cells, an ECHOvirus 6 chronic infection was established, resulting in altered extracellular glutamate uptake. This correlated with an aberrant splicing of the EAAT2 pre-messenger ribonucleic acid and a significant loss of EAAT2 protein expression, similar to that observed in patients with amyotrophic lateral sclerosis. These results provide convincing evidence that an enterovirus chronic/persistent infection may alter glial glutamate uptake and catabolism. As enteroviruses are extremely common human pathogens, they may act as a trigger in the development of certain motor neuron diseases, such as amyotrophic lateral sclerosis. ]


*9 : *Virus Res. 2001 Oct 30 ;78(1-2):57-66.

Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> *Functional changes in astrocytes by human T-lymphotropic virus type-1 T-lymphocytes.*

*Akaoka H* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Szymocha R* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Beurton-Marduel P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Bernard A* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Belin MF* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> .

Faculte de Medecine Laennec, Experimental Neurobiology and Physiopathology, INSERM U433, F69372 Cedex 08, Lyon, France.

The human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of a chronic progressive myelopathy (TSP/HAM) in which lesions of the central nervous system (CNS) are associated with infiltration of HTLV-1-infected T-cells. In a model that mimics the interaction between glial and T-cells, we show that transient contact with T-lymphocytes chronically infected with HTLV-1 induce profound metabolic alterations in astrocytes. Within the first week post-contact, an overall activation of astrocyte metabolism was observed as assessed by enhanced uptake of glutamate and glucose, and lactate release. In contrast, longer examination showed a reduced astrocytic accumulation of glutamate. The time course of the change in glutamate uptake was in fact biphasic. Previous observations indicated that HTLV-1 protein Tax-1 was involved in this delayed decrease, via the induction of TNF-alpha. The expression of the glial glutamate transporters, GLAST and GLT-1 decreased in parallel. These decreases in glutamate uptake and transporters’ expression were associated with an imbalance in the expression of the catabolic enzymes of glutamate, GS and GDH, presumably due to Tax-1. Given the fact that impairment of glutamate management in astrocytes is able to compromise the functional integrity of neurons and oligodendrocytes, our results altogether give new insights into the physiopathology of TSP/HAM.


*10 : *J Virol. 2001 Sep ;75(17):8268-82.

Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> *Morbillivirus infection of the mouse central nervous system induces region-specific upregulation of MMPs and TIMPs correlated to inflammatory cytokine expression.*

*Khuth ST* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Akaoka H* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Pagenstecher A* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Verlaeten O* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Belin MF* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Bernard A* <http://www.ncbi.nlm.nih.gov/entrez/...> .

INSERM U433, Neurobiologie Experimentale et Physiopathologie, Faculte de Medecine RTH Laennec, 69372 Lyon Cedex 08, France.

Viral infection of the central nervous system (CNS) can result in perturbation of cell-to-cell communication involving the extracellular matrix (ECM). ECM integrity is maintained by a dynamic balance between the synthesis and proteolysis of its components, mainly as a result of the action of matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). An MMP/TIMP imbalance may be critical in triggering neurological disorders, in particular in virally induced neural disorders. In the present study, a mouse model of brain infection using a neurotropic strain of canine distemper virus (CDV) was used to study the effect of CNS infection on the MMP/TIMP balance and cytokine expression. CDV replicates almost exclusively in neurons and has a unique pattern of expression (cortex, hypothalamus, monoaminergic nuclei, hippocampus, and spinal cord). Here we show that although several mouse brain structures were infected, they exhibited a differential pattern in terms of MMP, TIMP, and cytokine expression, exemplified by (i) a large increase in pro-MMP9 levels, in particular in the hippocampus, which occurred mainly in neurons and was associated with in situ gelatinolytic activity, (ii) specific and significant upregulation of MT1-MMP mRNA expression in the cortex and hypothalamus, (iii) an MMP/TIMP imbalance, suggested by the upregulation of TIMP-1 mRNA in the cortex, hippocampus, and hypothalamus and of TIMP-3 mRNA in the cortex, and (iv) a concomitant region-specific large increase in expression of Th1-like cytokines, such as gamma interferon, tumor necrosis factor alpha, and interleukin 6 (IL-6), contrasting with weaker induction of Th2-like cytokines, such as IL-4 and IL-10. These data indicate that an MMP/TIMP imbalance in specific brain structures, which is tightly associated with a local inflammatory process as shown by the presence of immune infiltrating cells, differentially impairs CNS integrity and may contribute to the multiplicity of late neurological disorders observed in this viral mouse model.


*11 : *Mol Cell Endocrinol. 2001 Jul 5 ;181(1-2):207-19.

Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> *Down regulation of melanin concentrating hormone in virally induced obesity.*

*Verlaeten O* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Griffond B* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Khuth ST* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Akaoka H* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Belin MF* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Fellmann D* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Bernard A* <http://www.ncbi.nlm.nih.gov/entrez/...> .

INSERM U433, Neurobiologie Experimentale et Physiopathologie, Faculte de Medecine RTH Laennec, rue Guillaume Paradin, 69372 Cedex 08, Lyon, France.

Obesity is a complex disease involving genetic components and environmental factors and probably associated with the dysregulation of central homeostasis normally maintained by the hypothalamic neuroendocrine/neurotransmitter network. We previously reported that canine distemper virus (CDV), which is closely related to human measles virus, can target hypothalamic nuclei, and lead to obesity syndrome in the late stages of infection. Here, using differential display PCR, we demonstrate specific down-regulation of melanin-concentrating hormone precursor mRNA (ppMCH) in infected-obese mice. Although ppMCH was down-regulated in all infected mice during the acute stage of infection, this was only seen during the late stage of infection in infected-obese mice. In addition, ppMCH mRNA and protein expression in the lateral hypothalamus was decreased in the absence of neuronal death. These results show the importance of ppMCH in the establishment and maintenance of obesity and the involvement of a virus as an environmental factor.


*12 : *AIDS Res Hum Retroviruses. 2000 Jul 1 ;16(10):965-72.

Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> *Tissue inhibitor of metalloproteinase 3, matrix metalloproteinase 9, and neopterin in the cerebrospinal fluid : preferential presence in HTLV type I-infected neurologic patients versus healthy virus carriers.*

*Lezin A* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Buart S* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Smadja D* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Akaoka H* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Bourdonne O* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Perret-Liaudet A* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Cesaire R* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Belin MF* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> .

ETS de La Martinique, Laboratoire de Virologie, Fort de France.

The human retrovirus HTLV-I is responsible for the chronic progressive myelopathy, TSP/HAM, characterized by the presence of infiltrated T lymphocytes, cytokines, and matrix metalloproteinases (MMPs) within spinal cord lesions. MMPs have been associated with several neurological diseases, and we previously reported the specific presence of the extracellular matrix-degrading protease, MMP-9, in the cerebrospinal fluid of TSP/HAM patients. Nevertheless, previous studies have not yet shown whether the expression of MMP-9 is associated with HTLV-I infection per se, or with neurological symptoms following infection. In the present work, the presence of tissue inhibitors of metalloproteinases 1 and 3 (TIMP-1 and TIMP-3) and of MMP-9 in the CSF of HTLV-I-infected individuals was compared in TSP/HAM patients versus HTLV-I carriers without neurological symptoms. TIMP-3, a regulator of MMP activity and cell survival, was detected with a significantly higher frequency in the TSP/HAM group and paralleled the increased levels of MMP-9 and neopterin, a sensitive indicator of cellular immune activation. These data may reflect the intense cell remodeling that occurs intrathecally in inflamed tissue. Changes in MMP, TIMP, and neopterin expression were not related to age at onset of disease, grade of motor disability, progressor status, or duration of disease, presumably indicating that TSP/HAM patients are continuously subjected to viral and immunological pressure. All these observations suggest that TIMPs and MMPs may contribute to the pathogenesis of TSP/HAM, and hence a new therapeutic strategy targeting the MMP/TIMP balance is needed. These observations also suggest that MMP-9 and TIMP-3 in CSF may be useful markers in the follow-up of the efficacy of therapeutic trials in TSP/HAM patients.

PMID : 10890358 [PubMed - indexed for MEDLINE]


*13 : *J Virol. 2000 Jul ;74(14):6433-41.

Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> *Human T-cell lymphotropic virus type 1-infected T lymphocytes impair catabolism and uptake of glutamate by astrocytes via Tax-1 and tumor necrosis factor alpha.*

*Szymocha R* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Akaoka H* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Dutuit M* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Malcus C* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Didier-Bazes M* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Belin MF* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> .

Experimental Neurobiology and Physiopathology Unit, INSERM U433, Lyon, France.

Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of a chronic progressive myelopathy called tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). In this disease, lesions of the central nervous system (CNS) are associated with perivascular infiltration by lymphocytes. We and others have hypothesized that these T lymphocytes infiltrating the CNS may play a prominent role in TSP/HAM. Here, we show that transient contact of human or rat astrocytes with T lymphocytes chronically infected by HTLV-1 impairs some of the major functions of brain astrocytes. Uptake of extracellular glutamate by astrocytes was significantly decreased after transient contact with infected T cells, while the expression of the glial transporters GLAST and GLT-1 was decreased. In two-compartment cultures avoiding direct cell-to-cell contact, similar results were obtained, suggesting possible involvement of soluble factors, such as cytokines and the viral protein Tax-1. Recombinant Tax-1 and tumor necrosis factor alpha (TNF-alpha) decreased glutamate uptake by astrocytes. Tax-1 probably acts by inducing TNF-alpha, as the effect of Tax-1 was abolished by anti-TNF-alpha antibody. The expression of glutamate-catabolizing enzymes in astrocytes was increased for glutamine synthetase and decreased for glutamate dehydrogenase, the magnitudes of these effects being correlated with the level of Tax-1 transcripts. In conclusion, Tax-1 and cytokines produced by HTLV-1-infected T cells impair the ability of astrocytes to manage the steady-state level of glutamate, which in turn may affect neuronal and oligodendrocytic functions and survival.

PMID : 10864655 [PubMed - indexed for MEDLINE]


*14 : *J Immunol. 2000 Mar 1 ;164(5):2718-27.

Click here to read <http://www.ncbi.nlm.nih.gov/entrez/...> *T lymphocytes activated by persistent viral infection differentially modify the expression of metalloproteinases and their endogenous inhibitors, TIMPs, in human astrocytes : relevance to HTLV-I-induced neurological disease.*

*Giraudon P* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Szymocha R* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Buart S* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Bernard A* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Cartier L* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Belin MF* <http://www.ncbi.nlm.nih.gov/entrez/...> , *Akaoka H* <http://www.ncbi.nlm.nih.gov/entrez/...> .

Institut National de la Sante et de la Recherche Medicale U433, Faculte de Medecine R. Laennec, Lyon, France. giraudon lyon151.inserm.fr

Activation of T lymphocytes by human pathogens is a key step in the development of immune-mediated neurologic diseases. Because of their ability to invade the CNS and their increased secretion of proinflammatory cytokines, activated CD4+ T cells are thought to play a crucial role in pathogenesis. In the present study, we examined the expression of inflammatory mediators the cytokine-induced metalloproteinases (MMP-2, -3, and -9) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMP-1, -2, and -3), in human astrocytes in response to activated T cells. We used a model system of CD4+ T lymphocytes activated by persistent viral infection (human T lymphotropic virus, HTLV-I) in transient contact with human astrocytes. Interaction with T cells resulted in increased production of MMP-3 and active MMP-9 in astrocytes despite increased expression of endogenous inhibitors, TIMP-1 and TIMP-3. These data suggest perturbation of the MMP/TIMP balance. These changes in MMP and TIMP expression were mediated, in part, by soluble factors (presumably cytokines) secreted by activated T cells. Integrin-mediated cell adhesion is also involved in the change in MMP level, since blockade of integrin subunits (alpha1, alpha3, alpha5, and beta1) on T cells resulted in less astrocytic MMP-9-induced expression. Interestingly, in CNS tissues from neurological HTLV-I-infected patients, MMP-9 was detected in neural cells within the perivascular space, which is infiltrated by mononuclear cells. Altogether, these data emphasize the importance of the MMP-TIMP axis in the complex interaction between the CNS and invading immune cells in the context of virally mediated T cell activation.

Bonsoir,

Voici également la bibliographie de l’ invitée du séminaire du 28 novembre, Pascale Giraudon. ( contact : Santiago Rivera tél : 04 91 69 89 65 )

Olivier Crouzet Bibliothèque universitaire de Médecine-Odontologie ( La Timone) 27, Bd Jean Moulin 13385 Marseille cedex 05 Tel 04 91 32 46 53 - Fax 04 91 79 41 15

Bibliothèque universitaire de Médecine-nord Bd Pierre Dramard 13916 Marseille cedex 20 Tel 04 91 69 89 50 & 04 91 69 89 52 - Fax 04 91 69 89 51

>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>

Docteur Pascale GIRAUDON Inserm U 433, Faculté de Médecine Laennec, Lyon.

CRMP2, un nouvel acteur de la mobilité lymphocytaire.

1 : Neuromolecular Med. 2005 ;7(3):207-16.

T-cells in neuronal injury and repair : semaphorins and related T-cell signals.

Giraudon P, Vincent P, Vuaillat C.

U433 Inserm, Neurobiologie Experimentale et Physiopathologie, Faculte de Medecine Laennec Rue Guillaume Paradin, 69372 Lyon Cedex 08, France.

There are many parallels between the hematopoietic and the nervous systems in terms of mechanisms regulating their development and functions. In neuroinflammatory diseases, interaction between the immune and nervous systems through shared molecules is suspected to trigger an inappropriate crosstalk and lead to demyelination and axonal loss. Here we focus on semaphorins and their functions in the nervous and immune systems and point out the deleterious effect of an immune semaphorin, semaphorin 4D (Sema4D)/CD100, on oligodendrocyte integrity and survival. We propose immune semaphorins as new candidates involved in the pathogenic mechanisms of neuroinflammatory diseases, promoting demyelination, and impairing neuroregeneration.


2 : J Neurochem. 2005 Sep ;94(6):1580-93. Epub 2005 Jul 18.

Impairment of blood-cerebrospinal fluid barrier properties by retrovirus-activated T lymphocytes : reduction in cerebrospinal fluid-to-blood efflux of prostaglandin E2.

Khuth ST, Strazielle N, Giraudon P, Belin MF, Ghersi-Egea JF.

INSERM U433, Universite Claude Bernard Lyon 1, Faculte de Medecine RTH Laennec, Lyon, France.

The choroid plexus epithelium forms the interface between the blood and the CSF. In conjunction with the tight junctions restricting the paracellular pathway, polarized specific transport systems in the choroidal epithelium allow a fine regulation of CSF-borne biologically active mediators. The highly vascularized stroma delimited by the choroidal epithelium can be a reservoir for retrovirus-infected or activated immune cells. In this work, new insight in the implication of the blood-CSF barrier in neuroinfectious and inflammatory diseases is provided by using a differentiated cellular model of the choroidal epithelium, exposed to infected T lymphocytes. We demonstrate that T cells activated by a retroviral infection, but not non-infected cells, reduce the transporter-mediated CSF-to-blood efflux of organic anions, in particular that of the potent pro-inflammatory prostaglandin PGE2, via the release of soluble factors. A moderate alteration of the paracellular permeability also occurs. We identified the viral protein Tax, oxygenated free radicals, matrix-metalloproteinases and pro-inflammatory cytokines as active molecules released during the exposure of the epithelium to infected T cells. Among them, tumour necrosis factor and interleukin 1 are directly involved in the mechanism underlying the decrease in some choroidal organic anion efflux. Given the strong involvement of CSF-borne PGE2 in sickness behaviour syndrome, these data suggest that the blood-CSF barrier plays an important role in the pathophysiology of neuroinflammation and neuroinfection, via changes in the transport processes controlling the CSF biodisposition of PGE2.


3 : Virus Genes. 2005 Jan ;30(1):103-12.

Cumulative mutations in the genome of Echovirus 6 during establishment of a chronic infection in precursors of glial cells.

Beaulieux F, Zreik Y, Deleage C, Sauvinet V, Legay V, Giraudon P, Kean KM, Lina B.

Laboratoire de Virologie, UMR CNRS 5537, Domaine Rockefeller, F-69373, Lyon cedex 08, France.

Although Enteroviruses are mainly described as responsible for acute diseases, their role in severe chronic pathology has been also established. Echovirus 6-like sequences have been detected by PCR analysis in central nervous system specimens from patients presenting with Amyotrophic Lateral Sclerosis. These findings suggested a persistent infection with viruses that underwent, genetic changes precluding viral particle release. To support this hypothesis, we developed a model system of Echovirus 6 chronic infection in precursors of glial cells. The nucleotide sequences of the 5’non-translated region (5’NTR), 2A and 3C regions of the virus developing persistent genome were analysed during establishment of the chronic phenotype. This study revealed that at day 160 of chronic infection, several mutations were observed : one mutation at nucleotide 108 upstream the domain II of the internal ribosome entry site (IRES) structure, one mutation at nucleotide 30 in the cloverleaf, and two mutations in the 2A region (translated in His48 to Tyr, and Ile 123 to Met). No mutations were detected in the 3C region. The impact of these mutations on viral replication have been analysed in a rabbit reticulocyte lysate (RRL) translation assay supplemented with HeLa cell lysate, and by plaque assay. Viruses with these mutations displayed a phenotype with a significant reduction of replication, while in vitro translation was not affected by the nucleotide 108 mutation. This model allowed the description of molecular changes observed in the genome of Echovirus 6 during the establishment of a chronic infection phenotype, and may be helpful for the understanding of the mechanisms leading Enteroviruses to develop chronic infections in man.


4 : Scand J Clin Lab Invest. 2004 Apr ;64(2):101-7. Extracellular matrix protein expression in cerebrospinal fluid from patients with tropical spastic paraparesis associated with HTLV-I and Creutzfeldt-Jakob disease.

Cartier L, Garcia L, Kettlun AM, Castaneda P, Collados L, Vasquez F, Giraudon P, Belin MF, Valenzuela MA.

Departamento de Ciencias Neurologicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.

The cerebrospinal fluid (CSF) is in direct contact with the extracellular space of the CNS, thus biochemical processes in the CNS could potentially be reflected in the CSF. Changes in extracellular matrix (ECM) proteins can be studied through their analysis in the CSF. ECM plays an essential role in CNS homeostasis and several proteins such as laminin (LN), fibronectin (FN), thrombospondin (TS) and heparan sulphate proteoglycan (HS, perlecan) form part of its structure. Possible changes in the levels of these proteins were investigated in two different pathologies—tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) (n=25) and Creutzfeldt-Jakob disease (CJD) (n=19)—and compared with those in a control group with or without neurological disease (n=25). CSF analyses were carried out using monoclonal or monospecific polyclonal antibodies. In comparison with the control group, it was found that TSP/HAM patients presented significantly higher levels of LN, TS and HS, while in CJD patients the levels of FN, TS and HS were increased. In CJD patients the HS level was almost double that of the TSP/HAM patients. These results suggest a distinct pattern of ECM proteins in CSF in relation to the type of neurological disease. TSP/HAM is a chronic motor disease that affects the white matter of the spinal cord, while CJD is a subacute dementia that affects cerebral neurons and their synapsis.


5 : J Immunol. 2004 Jan 15 ;172(2):1246-55.

Semaphorin CD100 from activated T lymphocytes induces process extension collapse in oligodendrocytes and death of immature neural cells.

Giraudon P, Vincent P, Vuaillat C, Verlaeten O, Cartier L, Marie-Cardine A, Mutin M, Bensussan A, Belin MF, Boumsell L.

INSERM Unit 433, Experimental Neurobiology and Physiopathology, Federative Institut of Neuroscience 19, Faculty of Medicine R Laennec, rue G. Paradin, 69372 Lyon CEDEX 08, France. giraudon lyon.inserm.fr

An inappropriate cross talk between activated T lymphocytes infiltrating the CNS and neural cells can sustain the onset and progression of demyelination and axonal degeneration in neuroinflammatory diseases. To mimic this deleterious cross talk, we designed an experimental paradigm consisting of transient cocultures of T lymphocytes chronically activated by retrovirus infection (not virus productive) with human multipotent neural precursors or primary oligodendrocytes from rat brain. We showed that activated T lymphocytes induced apoptotic death of multipotent neural progenitors and immature oligodendrocytes after a progressive collapse of their process extensions. These effects were reminiscent of those induced by brain semaphorin on neural cells. Blockade by specific Abs of soluble CD100 (sCD100)/semaphorin 4D released by activated T cells, or treatment with rsCD100, demonstrated that this immune semaphorin has the ability to collapse oligodendrocyte process extensions and to trigger neural cell apoptosis, most likely through receptors of the plexin family. The specific presence of sCD100 in the cerebrospinal fluid and of CD100-expressing T lymphocytes in the spinal cord of patients suffering with neuroinflammatory demyelination pointed to the potential pathological effect of sCD100 in the CNS. Thus, our results show that CD100 is a new important element in the deleterious T cell-neural cell cross talk during neuroinflammation and suggest its role in demyelination or absence of remyelination in neuroinflammatory diseases including multiple sclerosis and human T lymphotropic virus type 1-associated myelopathy.


6 : J Neuropathol Exp Neurol. 2003 Dec ;62(12):1254-64.

Pro-inflammatory cytokines modulate matrix metalloproteinase secretion and organic anion transport at the blood-cerebrospinal fluid barrier.

Strazielle N, Khuth ST, Murat A, Chalon A, Giraudon P, Belin MF, Ghersi-Egea JF.

Unite INSERM 433, Faculte de Medecine Laennec, Lyon, France.

Neuroinflammation and neuroinfection trigger cytokine-mediated responses that include an increase in the cerebrospinal fluid (CSF) levels of pro-inflammatory matrix metalloproteinases (MMPs) and organic anions such as leukotrienes and prostaglandins. The choroid plexus (CP) epithelium forming the interface between the blood and the CSF regulates the CSF concentration of bioactive organic anions and is involved in neuro-immune regulation. We demonstrated that both fourth and lateral ventricle CPs are a source of pro- and active MMP-2 and MMP-9 in the brain. Using a cellular model of the blood-CSF barrier, we showed that a pro-inflammatory cytokine treatment leads to an increase in the choroidal MMP secretion at either the apical or the basolateral membrane, depending on the ventricular origin of the choroidal cells. This effect was not concomitant with an alteration in the structural blood-CSF barrier. Neither was the pool of antioxidant sulfhydryls in the choroidal cells challenged. In contrast, the efficiency of the choroidal epithelium to clear the CSF from organic anions was highly reduced. Thus, during inflammation, the CPs could be one source of MMPs found in the CSF facilitate leucocyte migration by secreting MMPs into the choroidal stroma, and promote the inflammatory process by failing in its ability to clear deleterious compounds from the brain.


7 : J Soc Biol. 2003 ;197(2):103-12. [Astrocytes, cells involved in neuro-immune interactions in the central nervous system]

[Article in French]

Giraudon P, Malcus C, Chalon A, Vincent P, Khuth S, Bernard A, Belin MF.

Inserm U433 Faculte de Medecine R Laennec, 69372 Lyon. giraudon lyon.inserm.fr

The astrocyte, the major glial cell in the central nervous system, may influence many aspects of inflammation and immune reactivity within the brain. We have established a model of chronically activated T lymphocytes, interacting with neural cells of diverse origin to study the complex immune regulatory system suspected to lead to neuroinflammatory diseases. We show that human astrocytes became reactive following T cell contact, secreting proinflammatory cytokines, matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinase (TIMP). The altered MMP/TIMP system was shown to be involved in deleterious effects displayed by activated T cells towards human multipotent neural precursers by controlling their sensitivity to T cell-induced Fas-mediated apoptosis. MMP/TIMP was suspected to stabilize Fas at the cell membrane. In a model of mixed rat glial cells in primary culture (astrocytes, oligodendrocytes), activated T lymphocytes induced the collapse of processes and the death of immature oligodendrocytes. These effects were associated with upregulation of Fas at the cell surface of oligodendrocytes and secretion of MMP and TIMP by astrocytes. By amplifying the expression of inflammatory molecules including the MMP/TIMP system, astrocytes appear to be a crucial relay in the deleterious molecular cascade triggered by activated T lymphocytes. Detection of altered MMP/TIMP in patients suffering from myelopathy associated with retroviral infection (HTLV-1) strongly suggests its involvement in the physiopathological process of the disease.


8 : Eur J Neurosci. 2003 May ;17(9):1820-8.

Impaired glutamate uptake and EAAT2 downregulation in an enterovirus chronically infected human glial cell line.

Legay V, Deleage C, Beaulieux F, Giraudon P, Aymard M, Lina B.

UMR 5537, Laboratoire de Virologie Medicale, Domaine Rockefeller, Lyon, France.

Rapid and efficient uptake of glutamate via the high-affinity glutamate transporter EAAT2 is important for limiting glutamate-mediated excitotoxicity involved in neuronal death. Furthermore, there is evidence of altered glutamate uptake and catabolism in motor neuron diseases. Such a defect has been reported in amyotrophic lateral sclerosis, the major motor neuron disease, and was associated with impairment in EAAT2 processing. We recently reported the presence of enterovirus genome specifically in the anterior horn of amyotrophic lateral sclerosis cases, suggesting the involvement of a chronic/persistent enterovirus infection in amyotrophic lateral sclerosis. To investigate a putative link between enterovirus infection and the glutamate-mediated excitotoxicity observed in amyotrophic lateral sclerosis, we developed an in vitro model consisting of a human glial cell line infected with ECHOvirus 6, one of the enteroviruses with sequences closely related to those detected in patients with amyotrophic lateral sclerosis. In these glial cells, an ECHOvirus 6 chronic infection was established, resulting in altered extracellular glutamate uptake. This correlated with an aberrant splicing of the EAAT2 pre-messenger ribonucleic acid and a significant loss of EAAT2 protein expression, similar to that observed in patients with amyotrophic lateral sclerosis. These results provide convincing evidence that an enterovirus chronic/persistent infection may alter glial glutamate uptake and catabolism. As enteroviruses are extremely common human pathogens, they may act as a trigger in the development of certain motor neuron diseases, such as amyotrophic lateral sclerosis. ]


9 : Virus Res. 2001 Oct 30 ;78(1-2):57-66.

Functional changes in astrocytes by human T-lymphotropic virus type-1 T-lymphocytes.

Akaoka H, Szymocha R, Beurton-Marduel P, Bernard A, Belin MF, Giraudon P.

Faculte de Medecine Laennec, Experimental Neurobiology and Physiopathology, INSERM U433, F69372 Cedex 08, Lyon, France.

The human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of a chronic progressive myelopathy (TSP/HAM) in which lesions of the central nervous system (CNS) are associated with infiltration of HTLV-1-infected T-cells. In a model that mimics the interaction between glial and T-cells, we show that transient contact with T-lymphocytes chronically infected with HTLV-1 induce profound metabolic alterations in astrocytes. Within the first week post-contact, an overall activation of astrocyte metabolism was observed as assessed by enhanced uptake of glutamate and glucose, and lactate release. In contrast, longer examination showed a reduced astrocytic accumulation of glutamate. The time course of the change in glutamate uptake was in fact biphasic. Previous observations indicated that HTLV-1 protein Tax-1 was involved in this delayed decrease, via the induction of TNF-alpha. The expression of the glial glutamate transporters, GLAST and GLT-1 decreased in parallel. These decreases in glutamate uptake and transporters’ expression were associated with an imbalance in the expression of the catabolic enzymes of glutamate, GS and GDH, presumably due to Tax-1. Given the fact that impairment of glutamate management in astrocytes is able to compromise the functional integrity of neurons and oligodendrocytes, our results altogether give new insights into the physiopathology of TSP/HAM.


10 : J Virol. 2001 Sep ;75(17):8268-82.

Morbillivirus infection of the mouse central nervous system induces region-specific upregulation of MMPs and TIMPs correlated to inflammatory cytokine expression.

Khuth ST, Akaoka H, Pagenstecher A, Verlaeten O, Belin MF, Giraudon P, Bernard A.

INSERM U433, Neurobiologie Experimentale et Physiopathologie, Faculte de Medecine RTH Laennec, 69372 Lyon Cedex 08, France.

Viral infection of the central nervous system (CNS) can result in perturbation of cell-to-cell communication involving the extracellular matrix (ECM). ECM integrity is maintained by a dynamic balance between the synthesis and proteolysis of its components, mainly as a result of the action of matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). An MMP/TIMP imbalance may be critical in triggering neurological disorders, in particular in virally induced neural disorders. In the present study, a mouse model of brain infection using a neurotropic strain of canine distemper virus (CDV) was used to study the effect of CNS infection on the MMP/TIMP balance and cytokine expression. CDV replicates almost exclusively in neurons and has a unique pattern of expression (cortex, hypothalamus, monoaminergic nuclei, hippocampus, and spinal cord). Here we show that although several mouse brain structures were infected, they exhibited a differential pattern in terms of MMP, TIMP, and cytokine expression, exemplified by (i) a large increase in pro-MMP9 levels, in particular in the hippocampus, which occurred mainly in neurons and was associated with in situ gelatinolytic activity, (ii) specific and significant upregulation of MT1-MMP mRNA expression in the cortex and hypothalamus, (iii) an MMP/TIMP imbalance, suggested by the upregulation of TIMP-1 mRNA in the cortex, hippocampus, and hypothalamus and of TIMP-3 mRNA in the cortex, and (iv) a concomitant region-specific large increase in expression of Th1-like cytokines, such as gamma interferon, tumor necrosis factor alpha, and interleukin 6 (IL-6), contrasting with weaker induction of Th2-like cytokines, such as IL-4 and IL-10. These data indicate that an MMP/TIMP imbalance in specific brain structures, which is tightly associated with a local inflammatory process as shown by the presence of immune infiltrating cells, differentially impairs CNS integrity and may contribute to the multiplicity of late neurological disorders observed in this viral mouse model.


11 : Mol Cell Endocrinol. 2001 Jul 5 ;181(1-2):207-19.

Down regulation of melanin concentrating hormone in virally induced obesity.

Verlaeten O, Griffond B, Khuth ST, Giraudon P, Akaoka H, Belin MF, Fellmann D, Bernard A.

INSERM U433, Neurobiologie Experimentale et Physiopathologie, Faculte de Medecine RTH Laennec, rue Guillaume Paradin, 69372 Cedex 08, Lyon, France.

Obesity is a complex disease involving genetic components and environmental factors and probably associated with the dysregulation of central homeostasis normally maintained by the hypothalamic neuroendocrine/neurotransmitter network. We previously reported that canine distemper virus (CDV), which is closely related to human measles virus, can target hypothalamic nuclei, and lead to obesity syndrome in the late stages of infection. Here, using differential display PCR, we demonstrate specific down-regulation of melanin-concentrating hormone precursor mRNA (ppMCH) in infected-obese mice. Although ppMCH was down-regulated in all infected mice during the acute stage of infection, this was only seen during the late stage of infection in infected-obese mice. In addition, ppMCH mRNA and protein expression in the lateral hypothalamus was decreased in the absence of neuronal death. These results show the importance of ppMCH in the establishment and maintenance of obesity and the involvement of a virus as an environmental factor.


12 : AIDS Res Hum Retroviruses. 2000 Jul 1 ;16(10):965-72.

Tissue inhibitor of metalloproteinase 3, matrix metalloproteinase 9, and neopterin in the cerebrospinal fluid : preferential presence in HTLV type I-infected neurologic patients versus healthy virus carriers.

Lezin A, Buart S, Smadja D, Akaoka H, Bourdonne O, Perret-Liaudet A, Cesaire R, Belin MF, Giraudon P.

ETS de La Martinique, Laboratoire de Virologie, Fort de France.

The human retrovirus HTLV-I is responsible for the chronic progressive myelopathy, TSP/HAM, characterized by the presence of infiltrated T lymphocytes, cytokines, and matrix metalloproteinases (MMPs) within spinal cord lesions. MMPs have been associated with several neurological diseases, and we previously reported the specific presence of the extracellular matrix-degrading protease, MMP-9, in the cerebrospinal fluid of TSP/HAM patients. Nevertheless, previous studies have not yet shown whether the expression of MMP-9 is associated with HTLV-I infection per se, or with neurological symptoms following infection. In the present work, the presence of tissue inhibitors of metalloproteinases 1 and 3 (TIMP-1 and TIMP-3) and of MMP-9 in the CSF of HTLV-I-infected individuals was compared in TSP/HAM patients versus HTLV-I carriers without neurological symptoms. TIMP-3, a regulator of MMP activity and cell survival, was detected with a significantly higher frequency in the TSP/HAM group and paralleled the increased levels of MMP-9 and neopterin, a sensitive indicator of cellular immune activation. These data may reflect the intense cell remodeling that occurs intrathecally in inflamed tissue. Changes in MMP, TIMP, and neopterin expression were not related to age at onset of disease, grade of motor disability, progressor status, or duration of disease, presumably indicating that TSP/HAM patients are continuously subjected to viral and immunological pressure. All these observations suggest that TIMPs and MMPs may contribute to the pathogenesis of TSP/HAM, and hence a new therapeutic strategy targeting the MMP/TIMP balance is needed. These observations also suggest that MMP-9 and TIMP-3 in CSF may be useful markers in the follow-up of the efficacy of therapeutic trials in TSP/HAM patients.

PMID : 10890358 [PubMed - indexed for MEDLINE]


13 : J Virol. 2000 Jul ;74(14):6433-41.

Human T-cell lymphotropic virus type 1-infected T lymphocytes impair catabolism and uptake of glutamate by astrocytes via Tax-1 and tumor necrosis factor alpha.

Szymocha R, Akaoka H, Dutuit M, Malcus C, Didier-Bazes M, Belin MF, Giraudon P.

Experimental Neurobiology and Physiopathology Unit, INSERM U433, Lyon, France.

Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of a chronic progressive myelopathy called tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). In this disease, lesions of the central nervous system (CNS) are associated with perivascular infiltration by lymphocytes. We and others have hypothesized that these T lymphocytes infiltrating the CNS may play a prominent role in TSP/HAM. Here, we show that transient contact of human or rat astrocytes with T lymphocytes chronically infected by HTLV-1 impairs some of the major functions of brain astrocytes. Uptake of extracellular glutamate by astrocytes was significantly decreased after transient contact with infected T cells, while the expression of the glial transporters GLAST and GLT-1 was decreased. In two-compartment cultures avoiding direct cell-to-cell contact, similar results were obtained, suggesting possible involvement of soluble factors, such as cytokines and the viral protein Tax-1. Recombinant Tax-1 and tumor necrosis factor alpha (TNF-alpha) decreased glutamate uptake by astrocytes. Tax-1 probably acts by inducing TNF-alpha, as the effect of Tax-1 was abolished by anti-TNF-alpha antibody. The expression of glutamate-catabolizing enzymes in astrocytes was increased for glutamine synthetase and decreased for glutamate dehydrogenase, the magnitudes of these effects being correlated with the level of Tax-1 transcripts. In conclusion, Tax-1 and cytokines produced by HTLV-1-infected T cells impair the ability of astrocytes to manage the steady-state level of glutamate, which in turn may affect neuronal and oligodendrocytic functions and survival.

PMID : 10864655 [PubMed - indexed for MEDLINE]


14 : J Immunol. 2000 Mar 1 ;164(5):2718-27.

T lymphocytes activated by persistent viral infection differentially modify the expression of metalloproteinases and their endogenous inhibitors, TIMPs, in human astrocytes : relevance to HTLV-I-induced neurological disease.

Giraudon P, Szymocha R, Buart S, Bernard A, Cartier L, Belin MF, Akaoka H.

Institut National de la Sante et de la Recherche Medicale U433, Faculte de Medecine R. Laennec, Lyon, France. giraudon lyon151.inserm.fr

Activation of T lymphocytes by human pathogens is a key step in the development of immune-mediated neurologic diseases. Because of their ability to invade the CNS and their increased secretion of proinflammatory cytokines, activated CD4+ T cells are thought to play a crucial role in pathogenesis. In the present study, we examined the expression of inflammatory mediators the cytokine-induced metalloproteinases (MMP-2, -3, and -9) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMP-1, -2, and -3), in human astrocytes in response to activated T cells. We used a model system of CD4+ T lymphocytes activated by persistent viral infection (human T lymphotropic virus, HTLV-I) in transient contact with human astrocytes. Interaction with T cells resulted in increased production of MMP-3 and active MMP-9 in astrocytes despite increased expression of endogenous inhibitors, TIMP-1 and TIMP-3. These data suggest perturbation of the MMP/TIMP balance. These changes in MMP and TIMP expression were mediated, in part, by soluble factors (presumably cytokines) secreted by activated T cells. Integrin-mediated cell adhesion is also involved in the change in MMP level, since blockade of integrin subunits (alpha1, alpha3, alpha5, and beta1) on T cells resulted in less astrocytic MMP-9-induced expression. Interestingly, in CNS tissues from neurological HTLV-I-infected patients, MMP-9 was detected in neural cells within the perivascular space, which is infiltrated by mononuclear cells. Altogether, these data emphasize the importance of the MMP-TIMP axis in the complex interaction between the CNS and invading immune cells in the context of virally mediated T cell activation.

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