Mononuclear phagocyte differentiation, activation, and viral infection regulate matrix metalloproteinase expression: Implications for human immunodeficiency virus type 1-associated dementia
Mononuclear phagocyte differentiation, activation, and viral infection regulate matrix metalloproteinase expression: Implications for human immunodeficiency virus type 1-associated dementia
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DOI：
10.1128/jvi.75.14.6572-6583.2001
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发表时间：
2001-07-01
影响因子：
5.4
通讯作者：
Gendelman, HE
中科院分区：
文献类型：
--
作者：
Ghorpade, A;Persidskaia, R;Gendelman, HE
人类免疫缺陷病毒1型（HIV-1）相关性痴呆（HAD）的发病机制主要是由单核巨噬细胞（MP）分泌产物及其与神经细胞的相互作用介导的，病毒感染和R;IP免疫激活可影响白细胞进入脑。影响中枢神经系统（CNS）单核细胞迁移的一个因素是基质金属蛋白酶（MMPs）。在CNS中，MMPs由驻留的神经胶质细胞合成并影响神经胶质细胞外基质（ECM）的完整性。为了确定MMPs如何影响HAD发病机制，我们研究了它们在MP分化、病毒感染和细胞活化后的分泌。检测HIV-1感染的和/或免疫活化的单核细胞衍生的巨噬细胞（MDM）和人胎儿小胶质细胞的MMP-1、MMP-2、MMP-3和MMP-9的产生。MMP表达随MP分化程度的增加而增加。小胶质细胞分泌高水平的MMPs从头进一步升高后，CD 40配体介导的细胞活化。令人惊讶的是，HIV-1感染的MDM导致MMP-9的下调。在脑炎脑组织中，MMPs在血管周围和实质MP、多核巨细胞和小胶质细胞结节内表达。这些数据表明MP中MMP的产生依赖于细胞类型、分化、活化和/或病毒感染。这些因子对MMP表达的调节可能有助于HAD期间神经元ECM降解和白细胞迁移。
The pathogenesis of human immunodeficiency virus type 1 (HIV-l)-associated dementia (HAD) is mediated mainly by mononuclear phagocyte (MP) secretory products and their interactions with neural cells, Viral infection and R;IP immune activation may affect leukocyte entry into the brain. One factor that influences central nervous system (CNS) monocyte migration is matrix metalloproteinases (MMPs). In the CNS, MMPs are synthesized by resident glial cells and affect the integrity of the neuropil extracellular matrix (ECM). To ascertain how MMPs influence HAD pathogenesis, we studied their secretion following MP differentiation, viral infection, and cellular activation. HIV-l-infected and/or immune-activated monocyte-derived macrophages (MDM) and human fetal microglia were examined for production of MMP-1, -2, -3, and 9. MMP expression increased significantly with MP differentiation. Microglia secreted high levels of MMPs de novo that were further elevated following CD40 ligand-mediated cell activation. Surprisingly, HIV-1 infection of MDM led to the down-regulation of MMP-9. In encephalitic brain tissue, MMPs were expressed within perivascular and parenchymal MP, multinucleated giant cells, and microglial nodules. These data suggest that MMP production in MP is dependent on cell type, differentiation, activation, and/or viral infection. Regulation of MMP expression by these factors may contribute to neuropil ECM degradation and leukocyte migration during HAD.