HIV Infection Induces Extracellular Cathepsin B Uptake and Damage to Neurons.
Title | HIV Infection Induces Extracellular Cathepsin B Uptake and Damage to Neurons. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Cantres-Rosario, YM, Ortiz-RodrĂguez, SC, Santos-Figueroa, AG, Plaud, M, Negron, K, Cotto, B, Langford, D, MelĂ©ndez, LM |
Journal | Sci Rep |
Volume | 9 |
Issue | 1 |
Pagination | 8006 |
Date Published | 2019 05 29 |
ISSN | 2045-2322 |
Keywords | AIDS Dementia Complex, Apoptosis, Blood-Brain Barrier, Caspase 3, Cathepsin B, Cell Line, Cells, Cultured, Culture Media, Conditioned, Deoxyribonucleases, Type II Site-Specific, Endoribonucleases, Extracellular vesicles, Flow Cytometry, Hippocampus, Histidine, HIV Infections, HIV-1, Humans, Macrophages, Neoplasm Proteins, Neurons, Synaptophysin |
Abstract | HIV-associated neurocognitive disorders prevail in 20-50 percent of infected individuals. Macrophages transmigrate through the blood brain barrier during HIV-1 infection, triggering neuronal dysfunction. HIV-infected macrophages secrete cathepsin B (CATB), and serum amyloid p component (SAPC), inducing neuronal apoptosis by an unknown mechanism. We hypothesized that HIV infection facilitates CATB/SAPC secretion from macrophages followed by neuronal internalization, promoting dysfunction. SK-N-SH neuronal cells were exposed to active recombinant histidine-tagged cathepsin B (His-CATB). His-CATB entry was tracked by intracellular flow cytometry, and neuronal dysfunction was verified by western blot. Macrophage-derived extracellular vesicles (EVs) were tested for the presence of CATB and SAPC. Neurons internalized His-CATB, an effect that was partially decreased by pre-treatment with anti-CATB antibody. Pre-treatment with CATB and SAPC antibodies decreased cleavage of caspase-3 and restored synaptophysin in neurons. Neurons exposed to macrophage-conditioned media differentially internalized His-CATB, dependent on the HIV replication levels. Finally, CATB and SAPC were secreted in EVs. We report for the first time that CATB is secreted from macrophages both free and in EVs, and is internalized by neurons. Moreover, HIV-replication levels modulate the amount of CATB neuronal uptake, and neuronal dysfunction can be decreased with CATB antibodies. In conclusion, the CATB/SAPC complex represents a novel target against HIV-associated neurocognitive disorders. |
DOI | 10.1038/s41598-019-44463-1 |
Alternate Journal | Sci Rep |
PubMed ID | 31142756 |
PubMed Central ID | PMC6541605 |
Grant List | T32 MH079785 / MH / NIMH NIH HHS / United States U54 MD007600 / MD / NIMHD NIH HHS / United States U01 MH083506 / MH / NIMH NIH HHS / United States U54 MD007587 / MD / NIMHD NIH HHS / United States U01 MH083545 / MH / NIMH NIH HHS / United States U01 MH083500 / MH / NIMH NIH HHS / United States R25 GM061838 / GM / NIGMS NIH HHS / United States U24 MH100928 / MH / NIMH NIH HHS / United States SC1 GM113691 / GM / NIGMS NIH HHS / United States P01 DA037830 / DA / NIDA NIH HHS / United States U54 NS043011 / NS / NINDS NIH HHS / United States G12 MD007579 / MD / NIMHD NIH HHS / United States R01 MH107340 / MH / NIMH NIH HHS / United States U01 MH083507 / MH / NIMH NIH HHS / United States P30 MH092177 / MH / NIMH NIH HHS / United States U01 MH083501 / MH / NIMH NIH HHS / United States |