HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration
| Autor: | Janet Holden, G. Angus McQuibban, Christopher Power, Georgina S. Butler, Christopher M. Overall, James B. Johnston, Kunyan Zhang, Ian Clark-Lewis, Claudia Silva |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Chemokine
AIDS Dementia Complex Stromal cell Neurotoxins Inflammation Matrix Metalloproteinase Inhibitors Biology Matrix metalloproteinase Antibodies Cell Line Mice Zymogen medicine Animals Humans Stromal cell-derived factor 1 Enzyme Inhibitors Metalloproteinase Macrophages General Neuroscience Neurodegeneration medicine.disease Chemokine CXCL12 Peptide Fragments Neostriatum Disease Models Animal Astrocytes Nerve Degeneration Immunology HIV-1 biology.protein Cancer research Encephalitis Matrix Metalloproteinase 2 medicine.symptom Chemokines CXC Neuroscience |
| Zdroj: | Nature Neuroscience. 6:1064-1071 |
| ISSN: | 1546-1726 1097-6256 |
| DOI: | 10.1038/nn1127 |
| Popis: | The mechanisms of neurodegeneration that result in human immunodeficiency virus (HIV) type 1 dementia have not yet been identified. Here, we report that HIV-infected macrophages secrete the zymogen matrix metalloproteinase-2 (MMP-2), which is activated by exposure to MT1-MMP on neurons. Stromal cell-derived factor 1 alpha (SDF-1), a chemokine overexpressed by astrocytes during HIV infection, was converted to a highly neurotoxic protein after precise proteolytic processing by active MMP-2, which removed the N-terminal tetrapeptide. Implantation of cleaved SDF-1(5-67) into the basal ganglia of mice resulted in neuronal death and inflammation with ensuing neurobehavioral deficits that were abrogated by neutralizing antibodies to SDF-1 and an MMP inhibitor drug. Hence, this study identifies a new in vivo neurotoxic pathway in which cleavage of a chemokine by an induced metalloproteinase results in neuronal apoptosis that leads to neurodegeneration. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|