HIV-infected microglia mediate cathepsin B-induced neurotoxicity.
Title | HIV-infected microglia mediate cathepsin B-induced neurotoxicity. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Zenón, F, Cantres-Rosario, Y, Adiga, R, Gonzalez, M, Rodriguez-Franco, E, Langford, D, Meléndez, LM |
Journal | J Neurovirol |
Volume | 21 |
Issue | 5 |
Pagination | 544-58 |
Date Published | 2015 Oct |
ISSN | 1538-2443 |
Keywords | AIDS Dementia Complex, Apoptosis, Blotting, Western, Cathepsin B, Cell Line, Cells, Cultured, Cystatin B, Cystatin C, Enzyme-Linked Immunosorbent Assay, External, Flow Cytometry, Fluorescent Antibody Technique, HIV-1, Humans, In Situ Nick-End Labeling, Microglia, Neurons |
Abstract | HIV-1-infected mononuclear phagocytes release soluble factors that affect the homeostasis in tissue. HIV-1 can prompt metabolic encephalopathy with the addition of neuronal dysfunction and apoptosis. Recently, we reported that HIV-1 enhances the expression and secretion of bioactive cathepsin B in monocyte-derived macrophages, ultimately contributing to neuronal apoptosis. In this research, we asked if microglia respond to HIV infection similarly by modifying the expression, secretion, and neurotoxic potential of cathepsin B and determined the in vivo relevance of these findings. HIV-1ADA-infected human primary microglia and CHME-5 microglia cell line were assessed for expression and activity of cathepsin B, its inhibitors, cystatins B and C, and the neurotoxicity associated with these changes. Human primary neurons were exposed to supernatants from HIV-infected and uninfected microglia in the presence of cathepsin B inhibitors and apoptosis was assessed by TUNEL. Microglial expression of cathepsin B was validated in brain tissue from HIV encephalitis (HIVE) patients. HIV-infected microglia secreted significantly greater levels of cathepsin B, cystatin B, and cystatin C compared to uninfected cells. Increased apoptosis was observed in neurons exposed to supernatants from HIV-1 infected microglia at day 12 post-infection. The cathepsin B inhibitor CA-074 and cathepsin B antibody prevented neuronal apoptosis. Increased microglia-derived cathepsin B, cystatin B, and cystatin C and caspase-3+ neurons were detected in HIVE brains compared to controls. Our results suggest that HIV-1-induced cathepsin B production in microglia contributes to neuronal apoptosis and may be an important factor in neuronal death associated with HIVE. |
DOI | 10.1007/s13365-015-0358-7 |
Alternate Journal | J Neurovirol |
PubMed ID | 26092112 |
PubMed Central ID | PMC4618197 |
Grant List | U24 MH100929 / MH / NIMH NIH HHS / United States U01 MH083507 / MH / NIMH NIH HHS / United States R24 MH059724 / MH / NIMH NIH HHS / United States U01 MH083500 / MH / NIMH NIH HHS / United States U24 MH100931 / MH / NIMH NIH HHS / United States R01MH083516 / MH / NIMH NIH HHS / United States R24 NS045491 / NS / NINDS NIH HHS / United States N01MH32002 / MH / NIMH NIH HHS / United States U54NS4301 / NS / NINDS NIH HHS / United States R25 GM061838 / GM / NIGMS NIH HHS / United States U24 MH100928 / MH / NIMH NIH HHS / United States 5U01MH083500 / MH / NIMH NIH HHS / United States R24MH59724 / MH / NIMH NIH HHS / United States R24 MH059745 / MH / NIMH NIH HHS / United States R24MH59745 / MH / NIMH NIH HHS / United States R24 NS038841 / NS / NINDS NIH HHS / United States HD8G12-MD007600 / HD / NICHD NIH HHS / United States R24 NS45491 / NS / NINDS NIH HHS / United States NS 38841 / NS / NINDS NIH HHS / United States SC1GM11369-01 / GM / NIGMS NIH HHS / United States R25GM061838 / GM / NIGMS NIH HHS / United States G12 RR003051 / RR / NCRR NIH HHS / United States S06 GM008224 / GM / NIGMS NIH HHS / United States U01MH083501 / MH / NIMH NIH HHS / United States U01 MH083501 / MH / NIMH NIH HHS / United States SC1 GM113691 / GM / NIGMS NIH HHS / United States U01MH083506 / MH / NIMH NIH HHS / United States U01 MH083545 / MH / NIMH NIH HHS / United States U01 MH083506 / MH / NIMH NIH HHS / United States R01 MH083516 / MH / NIMH NIH HHS / United States GM08224 / GM / NIGMS NIH HHS / United States U01MH083507 / MH / NIMH NIH HHS / United States G12 MD007600 / MD / NIMHD NIH HHS / United States U01MH083545 / MH / NIMH NIH HHS / United States |