Production and Roles of Glial Tissue Inhibitor of Metalloproteinases-1 in Human Immunodeficiency Virus-1-Associated Dementia Neuroinflammation: A Review

Abstract

Problem statement: Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) and its cognate targets, the Matrix Metalloproteinases (MMPs), were differentially expressed in human brain samples with or without HIV-1 infection or HIV-1 Encephalitis (HIVE). Approach: A through literature review demonstrated that cell culture models of Central Nervous System (CNS) cell types had been used to illustrate the intricate temporal patterns of TIMP-1/MMP expression, regulated by a variety of inflammatory cytokines. Results: As MMPs and TIMP-1 can significantly altered the extracellular environment and cell signaling, the differential regulation of TIMP-1/MMP expression in neuroinflammation can impact neuronal function and survival in disease conditions. TIMP-1 prosurvival effects had been demonstrated in a variety of cell types including CNS neurons, protecting cells from a wide range of stress and insults. TIMP-1, also known to interact with non-MMP targets, altered cell behavior. In this review, we discussed the possibility that the upregulation of TIMP-1 by glia in acute neuroinflammation may be a neuroprotective response. Conclusion: It will be important to delineate the effects of TIMP-1 on neurons and identify receptors and downstream signaling pathways, in order to evaluate TIMP-1 as a therapeutic strategy for neuroinflammatory and neurodegenerative diseases.

PPAR Agonist-Mediated Protection against HIV Tat-Induced Cerebrovascular Toxicity is Enhanced in MMP-9-Deficient Mice

“…30 In addition, the neurotoxicity induced by Tat was inhibited by anti-MMP antibodies, but not by antibodies against Tat, indicating that Tat causes neuronal death through an indirect mechanism. 17 Our previous study indicated that Tat exposure upregulated MMP-9 protein levels in brain endothelial cells 14,15 and administration of Tat into the ICA enhanced MMP-9 activity in plasma and protein expression in brain tissue. 19 The mechanisms by which MMPs disrupt the barrier integrity of the brain endothelium appear to involve degradation of specific TJ proteins; therefore, it was surprising to show in the present study that the baseline Figure 5.…”

“…16 In fact, it was showed that Tat-induced neurotoxicity can be prevented by an MMP inhibitor, prinomastat, and upregulation of TIMP-1 by glia in acute HIV-1 infection may exhibit neuroprotection. 17 Because targeting both PPAR and MMP activities may alleviate HIV-1-induced neuropathology, we focused the present study on the interactions of these factors in a model of HIV cerebral toxicity induced by HIV-specific protein Tat. Our data indicate that Tat-induced disruption of the blood-brain barrier (BBB), alterations in TJ protein expression as well as neuronal loss and astrogliosis can be attenuated by PPAR agonists and MMP-9 deficiency.…”

Hepatitis C virus infection: a risk factor for Parkinson's disease

“…In addition, we found that TIMP‐1 was down‐regulated by HCV. TIMP‐1 is an important marker for neuroinflammatory and neurodegenerative diseases . TIMP‐1 is known to aid cell survival.…”

Genetic variation of MMP‐2(‐735 C>T) and MMP‐9(‐1562 C>T) gene in risk of development of HAND and severity of HAND

“…Protection against a disrupted BBB in HIV‐1 infection has not been described well. An imbalance between MMPs and endogenous TIMPs (tissue inhibitors of MMPs) may contribute to HIV‐associated pathology by inducing a remodeling of the extracellular matrix . One study showed that Tat‐induced neurotoxicity can be prevented by an MMP inhibitor, prinomastat, and also that upregulation of TIMP‐1 by glia in acute HIV‐1 infection may exhibit neuroprotection .…”

“…An imbalance between MMPs and endogenous TIMPs (tissue inhibitors of MMPs) may contribute to HIV-associated pathology by inducing a remodeling of the extracellular matrix. 28 One study showed that Tat-induced neurotoxicity can be prevented by an MMP inhibitor, prinomastat, and also that upregulation of TIMP-1 by glia in acute HIV-1 infection may exhibit neuroprotection. 29 Recent studies indicate that natural sequence variations including SNPs in promoters and coding regions, especially nonsynonymous SNPs of the MMP genes, may result in the differential expression of MMPs in different individuals.…”