Dysregulation of macrophage-secreted cathepsin B contributes to HIV-1-linked neuronal apoptosis.
Enviado por Loyda Milagros Melendez, Ph.D. el
Título | Dysregulation of macrophage-secreted cathepsin B contributes to HIV-1-linked neuronal apoptosis. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Autores | Rodriguez-Franco, EJ, Cantres-Rosario, YM, Plaud-Valentin, M, Romeu, R, Rodríguez, Y, Skolasky, R, Meléndez, V, Cadilla, C, Melendez, LM |
Journal | PLoS One |
Volume | 7 |
Issue | 5 |
Pagination | e36571 |
Date Published | 2012 |
ISSN | 1932-6203 |
Palabras clave | Apoptosis, Basal Ganglia, Cathepsin B, Cell Line, Tumor, Cognition, Cystatin B, Cystatin C, Female, Gene Expression Regulation, Enzymologic, Hippocampus, HIV-1, Humans, Intracellular Space, Lysosomes, Macrophages, Monocytes, Neurons |
Abstract | Chronic HIV infection leads to the development of cognitive impairments, designated as HIV-associated neurocognitive disorders (HAND). The secretion of soluble neurotoxic factors by HIV-infected macrophages plays a central role in the neuronal dysfunction and cell death associated with HAND. One potentially neurotoxic protein secreted by HIV-1 infected macrophages is cathepsin B. To explore the potential role of cathepsin B in neuronal cell death after HIV infection, we cultured HIV-1(ADA) infected human monocyte-derived macrophages (MDM) and assayed them for expression and activity of cathepsin B and its inhibitors, cystatins B and C. The neurotoxic activity of the secreted cathepsin B was determined by incubating cells from the neuronal cell line SK-N-SH with MDM conditioned media (MCM) from HIV-1 infected cultures. We found that HIV-1 infected MDM secreted significantly higher levels of cathepsin B than did uninfected cells. Moreover, the activity of secreted cathepsin B was significantly increased in HIV-infected MDM at the peak of viral production. Incubation of neuronal cells with supernatants from HIV-infected MDM resulted in a significant increase in the numbers of apoptotic neurons, and this increase was reversed by the addition of either the cathepsin B inhibitor CA-074 or a monoclonal antibody to cathepsin B. In situ proximity ligation assays indicated that the increased neurotoxic activity of the cathepsin B secreted by HIV-infected MDM resulted from decreased interactions between the enzyme and its inhibitors, cystatins B and C. Furthermore, preliminary in vivo studies of human post-mortem brain tissue suggested an upregulation of cathepsin B immunoreactivity in the hippocampus and basal ganglia in individuals with HAND. Our results demonstrate that HIV-1 infection upregulates cathepsin B in macrophages, increases cathepsin B activity, and reduces cystatin-cathepsin interactions, contributing to neuronal apoptosis. These findings provide new evidence for the role of cathepsin B in neuronal cell death induced by HIV-infected macrophages. |
DOI | 10.1371/journal.pone.0036571 |
Alternate Journal | PLoS ONE |
PubMed ID | 22693552 |
PubMed Central ID | PMC3365072 |
Grant List | 2G12-RR003051/HD 8G12-MD007600 / HD / NICHD NIH HHS / United States 5U01MH083500 / MH / NIMH NIH HHS / United States DBI-0923132 / / PHS HHS / United States ISI0 RR-13705-01 / RR / NCRR NIH HHS / United States N01MH32002 / MH / NIMH NIH HHS / United States NS 38841 / NS / NINDS NIH HHS / United States R01 MH083516 / MH / NIMH NIH HHS / United States R01MH083516 / MH / NIMH NIH HHS / United States R24 NS45491 / NS / NINDS NIH HHS / United States R24MH59724 / MH / NIMH NIH HHS / United States R24MH59745 / MH / NIMH NIH HHS / United States R25 GM061838 / GM / NIGMS NIH HHS / United States R25GM061838 / GM / NIGMS NIH HHS / United States S06GM08224 / GM / NIGMS NIH HHS / United States U01MH083501 / MH / NIMH NIH HHS / United States U01MH083506 / MH / NIMH NIH HHS / United States U01MH083507 / MH / NIMH NIH HHS / United States U01MH083545 / MH / NIMH NIH HHS / United States U54NS043011 / NS / NINDS NIH HHS / United States |