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 i nfiltrated within the CNS are suspected of playing a prominent role in path ogenesis via inflammatory cytokines and the viral protein Tax1, We hypothes ized that T lymphocytes initiate functional perturbation in astrocytes, res ulting in neuronal alteration as glial cells have a crucial role in CNS hom eostasis, In particular, astrocytes manage the steady state level of glutam ate and continuously provide metabolite precursors to neurons and oligodend rocytes, Using a model system of HTLV-1-infected T cells-astrocytes interac tion, we show that after contact with T cells, astrocyte acquire a phenotyp e typical of gliosis: secretion of proinflammatory cytokines (TNF-alpha, IL -1 alpha, IL-6) and matrix metalloproteinases (MMP-9, MMP3). The concomitan t increase in the expression of MMPs and of their endogenous inhibitors (TI MP-1 and TIMP-3) suggests a perturbation in MMP/TIMP balance. This may alte r the extracellular matrix and, in turn, the cell environment. At a functio nal level, glutamate transport and catabolism are impaired in astrocytes, A decrease in glutamate uptake is associated with downregulated expression o f glutamate transporters GLAST and GLT1. The expression of astrocytic enzym e of glutamate metabolism is modified with up-regulation of glutamine synth etase and down-regulation of glutamate dehydrogenase. The involvement of Ta x-1 in these alterations, directly or indirectly via TNF-alpha, is shown. A ltered glutamate uptake and catabolism associated with impairment in cell c onnectivity via MMP/TIMP imbalance could compromise the functional integrit y of the CNS in general and that of neurons and oligodendrocytes in particu lar.