Astrocytic alterations induced by HTLV type 1-infected T lymphocytes: a role for Tax-1 and tumor necrosis factor alpha.
In the neurological disease associated with HTLV-1 infected T lymphocytes infiltrated within the CNS are suspected of playing a prominent role in pathogenesis via inflammatory cytokines and the viral protein Tax-1. We hypothesized that T lymphocytes initiate functional perturbation in astrocytes, resulting in neuronal alteration as glial cells have a crucial role in CNS homeostasis. In particular, astrocytes manage the steady state level of glutamate and continuously provide metabolite precursors to neurons and oligodendrocytes. Using a model system of HTLV-1-infected T cells-astrocytes interaction, we show that after contact with T cells, astrocyte acquire a phenotype typical of gliosis: secretion of proinflammatory cytokines (TNF-alpha, IL-1alpha, IL-6) and matrix metalloproteinases (MMP-9, MMP-3). The concomitant increase in the expression of MMPs and of their endogenous inhibitors (TIMP-1 and TIMP-3) suggests a perturbation in MMP/TIMP balance. This may alter the extracellular matrix and, in turn, the cell environment. At a functional level, glutamate transport and catabolism are impaired in astrocytes. A decrease in glutamate uptake is associated with downregulated expression of glutamate transporters GLAST and GLT1. The expression of astrocytic enzyme of glutamate metabolism is modified with up-regulation of glutamine synthetase and down-regulation of glutamate dehydrogenase. The involvement of Tax-1 in these alterations, directly or indirectly via TNF-alpha, is shown. Altered glutamate uptake and catabolism associated with impairment in cell connectivity via MMP/TIMP imbalance could compromise the functional integrity of the CNS in general and that of neurons and oligodendrocytes in particular.
Szymocha
R
R
U433 INSERM, Faculté de Médecine R. Laënnec, 69372 Lyon, France.
Akaoka
H
H
Brisson
C
C
Beurton-Marduel
P
P
Chalon
A
A
Bernard
A
A
Didier-Bazes
M
M
Belin
M F
MF
Giraudon
P
P
D000818:Animals; D001253:Astrocytes / Q000473:pathology* / Q000502:physiology / Q000821:virology; D002460:Cell Line; D016356:Gene Products, tax / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D015493:Paraparesis, Tropical Spastic / Q000473:pathology* / Q000821:virology; D051381:Rats; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016356:Gene Products, tax; D005971:Glutamates; D014409:Tumor Necrosis Factor-alpha