Szymocha R, Akaoka H, Brisson C, Beurton-Marduel P, Chalon A, Bernard A, Didier-Bazes M, Belin M F, Giraudon P
U433 INSERM, Faculté de Médecine R. Laënnec, 69372 Lyon, France.
AIDS Res Hum Retroviruses. 2000 Nov 1;16(16):1723-9. doi: 10.1089/08892220050193218.
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.
在与人类嗜T淋巴细胞病毒1型（HTLV-1）相关的神经系统疾病中，怀疑浸润于中枢神经系统（CNS）内的被HTLV-1感染的T淋巴细胞通过炎性细胞因子和病毒蛋白Tax-1在发病机制中发挥重要作用。我们推测T淋巴细胞引发星形胶质细胞的功能紊乱，由于神经胶质细胞在CNS稳态中起关键作用，进而导致神经元改变。特别是，星形胶质细胞控制谷氨酸的稳态水平，并持续为神经元和少突胶质细胞提供代谢前体。利用HTLV-1感染的T细胞与星形胶质细胞相互作用的模型系统，我们发现与T细胞接触后，星形胶质细胞获得了典型的胶质增生表型：分泌促炎细胞因子（肿瘤坏死因子-α、白细胞介素-1α、白细胞介素-6）和基质金属蛋白酶（MMP-9、MMP-3）。MMP及其内源性抑制剂（TIMP-1和TIMP-3）表达的同时增加提示MMP/TIMP平衡受到干扰。这可能会改变细胞外基质，进而改变细胞环境。在功能水平上，星形胶质细胞中的谷氨酸转运和分解代谢受损。谷氨酸摄取减少与谷氨酸转运体GLAST和GLT1的表达下调有关。谷氨酸代谢的星形胶质细胞酶的表达发生改变，谷氨酰胺合成酶上调，谷氨酸脱氢酶下调。研究表明Tax-1直接或通过肿瘤坏死因子-α间接参与了这些改变。与通过MMP/TIMP失衡导致的细胞连接受损相关的谷氨酸摄取和分解代谢改变，可能会损害整个CNS的功能完整性，尤其是神经元和少突胶质细胞的功能完整性。
