Regulation of tissue inhibitor of metalloproteinase-1 by astrocytes: links to HIV-1 dementia.
The neuropathogenesis of HIV-1-associated dementia (HAD) revolves around the secretion of toxic molecules from infected and immune-competent mononuclear phagocytes. Astrocyte activation occurs in parallel but limited insights are available for its role in neurotoxicity and cognitive dysfunction. One means in which astrocytes may affect disease is through their production of tissue inhibitors of metalloproteinases (TIMPs). TIMPs are regulators of matrix metalloproteinases, enzymes that affect blood-brain barrier integrity through altering the extracellular matrix. We hypothesized that in response to injury and inflammation in HAD, astrocytes regulate the production of TIMP-1, the inducible type of TIMP that is important in inflammation. To address astrocyte-mediated TIMP-1 regulation in HAD, we evaluated the responses of primary human to IL-1beta and HIV-1. TIMP-1 levels in plasma, CSF, and brain tissue of control, HIV-1 infected patients without cognitive impairment, and HAD patients were also studied. Our data show that an upregulation of TIMP-1 results from astrocytes acutely activated with IL-1beta. In contrast, CSF and brain tissue samples from HAD patients showed reduced TIMP-1 levels compared to seronegative controls. MMP-2 levels in brains showed the opposite. Consistent with this, prolonged activation of astrocytes led to a reduction in TIMP-1 and MMP-2, but a sustained elevation in MMP-1. Our data suggest that in diseased brain tissue, the ability of astrocytes to counteract the destructive effects of MMP through expression of TIMP-1 is diminished by chronic activation. Our studies reveal new opportunities for repair-based therapeutic strategies in HAD.
Suryadevara
Radhika
R
Laboratory of Cellular Neuroimmunology, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Holter
Spring
S
Borgmann
Kathleen
K
Persidsky
Raisa
R
Labenz-Zink
Christine
C
Persidsky
Yuri
Y
Gendelman
Howard E
HE
Wu
Li
L
Ghorpade
Anuja
A
D015526:AIDS Dementia Complex / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D001253:Astrocytes / Q000201:enzymology*; D001921:Brain / Q000201:enzymology* / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004660:Encephalitis / Q000201:enzymology* / Q000276:immunology / Q000821:virology; D005333:Fetus; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000201:enzymology* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000821:virology; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D005904:Glial Fibrillary Acidic Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1