Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages
HIV-associated neurocognitive disorders (HAND) affect 15–55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated an increased expression of cathepsin B (CATB)...
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/6/3246 |
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| author | Lester J. Rosario-Rodríguez Yadira M. Cantres-Rosario Kelvin Carrasquillo-Carrión Ana E. Rodríguez-De Jesús Luz J. Cartagena-Isern Luis A. García-Requena Abiel Roche-Lima Loyda M. Meléndez |
| author_facet | Lester J. Rosario-Rodríguez Yadira M. Cantres-Rosario Kelvin Carrasquillo-Carrión Ana E. Rodríguez-De Jesús Luz J. Cartagena-Isern Luis A. García-Requena Abiel Roche-Lima Loyda M. Meléndez |
| author_sort | Lester J. Rosario-Rodríguez |
| collection | DOAJ |
| description | HIV-associated neurocognitive disorders (HAND) affect 15–55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated an increased expression of cathepsin B (CATB), a lysosomal protease, in monocytes and post-mortem brain tissues of women with HAND. Increased CATB release from HIV-infected MDM leads to neurotoxicity, and their secretion is associated with NF-κB activation, oxidative stress, and lysosomal exocytosis. Cannabinoid receptor 2 (CB2R) agonist, JWH-133, decreases HIV-1 replication, CATB secretion, and neurotoxicity from HIV-infected MDM, but the mechanisms are not entirely understood. We hypothesized that HIV-1 infection upregulates the expression of proteins associated with oxidative stress and that a CB2R agonist could reverse these effects. MDM were isolated from healthy women donors (<i>n</i> = 3), infected with HIV-1<sub>ADA</sub>, and treated with JWH-133. After 13 days post-infection, cell lysates were labeled by Tandem Mass Tag (TMT) and analyzed by LC/MS/MS quantitative proteomics bioinformatics. While HIV-1 infection upregulated CATB, NF-κB signaling, Nrf2-mediated oxidative stress response, and lysosomal exocytosis, JWH-133 treatment downregulated the expression of the proteins involved in these pathways. Our results suggest that JWH-133 is a potential alternative therapy against HIV-induced neurotoxicity and warrant in vivo studies to test its potential against HAND. |
| first_indexed | 2024-04-24T18:11:54Z |
| format | Article |
| id | doaj.art-eb0c4c893fa549a1a865cf276e77c567 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T18:11:54Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-eb0c4c893fa549a1a865cf276e77c5672024-03-27T13:45:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01256324610.3390/ijms25063246Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected MacrophagesLester J. Rosario-Rodríguez0Yadira M. Cantres-Rosario1Kelvin Carrasquillo-Carrión2Ana E. Rodríguez-De Jesús3Luz J. Cartagena-Isern4Luis A. García-Requena5Abiel Roche-Lima6Loyda M. Meléndez7Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan 00935, Puerto RicoTranslational Proteomics Center, Center for Collaborative Research in Health Disparities, University of Puerto Rico-Medical Sciences Campus, San Juan 00935, Puerto RicoIntegrated Informatics Core, Center for Collaborative Research in Health Disparities, University of Puerto Rico-Medical Sciences Campus, San Juan 00935, Puerto RicoTranslational Proteomics Center, Center for Collaborative Research in Health Disparities, University of Puerto Rico-Medical Sciences Campus, San Juan 00935, Puerto RicoDepartment of Biology, University of Puerto Rico-Río Piedras Campus, San Juan 00925, Puerto RicoDepartment of Biology, University of Puerto Rico-Río Piedras Campus, San Juan 00925, Puerto RicoIntegrated Informatics Core, Center for Collaborative Research in Health Disparities, University of Puerto Rico-Medical Sciences Campus, San Juan 00935, Puerto RicoDepartment of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan 00935, Puerto RicoHIV-associated neurocognitive disorders (HAND) affect 15–55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated an increased expression of cathepsin B (CATB), a lysosomal protease, in monocytes and post-mortem brain tissues of women with HAND. Increased CATB release from HIV-infected MDM leads to neurotoxicity, and their secretion is associated with NF-κB activation, oxidative stress, and lysosomal exocytosis. Cannabinoid receptor 2 (CB2R) agonist, JWH-133, decreases HIV-1 replication, CATB secretion, and neurotoxicity from HIV-infected MDM, but the mechanisms are not entirely understood. We hypothesized that HIV-1 infection upregulates the expression of proteins associated with oxidative stress and that a CB2R agonist could reverse these effects. MDM were isolated from healthy women donors (<i>n</i> = 3), infected with HIV-1<sub>ADA</sub>, and treated with JWH-133. After 13 days post-infection, cell lysates were labeled by Tandem Mass Tag (TMT) and analyzed by LC/MS/MS quantitative proteomics bioinformatics. While HIV-1 infection upregulated CATB, NF-κB signaling, Nrf2-mediated oxidative stress response, and lysosomal exocytosis, JWH-133 treatment downregulated the expression of the proteins involved in these pathways. Our results suggest that JWH-133 is a potential alternative therapy against HIV-induced neurotoxicity and warrant in vivo studies to test its potential against HAND.https://www.mdpi.com/1422-0067/25/6/3246CATBHIVMDMCB2RNF-κBNrf2 |
| spellingShingle | Lester J. Rosario-Rodríguez Yadira M. Cantres-Rosario Kelvin Carrasquillo-Carrión Ana E. Rodríguez-De Jesús Luz J. Cartagena-Isern Luis A. García-Requena Abiel Roche-Lima Loyda M. Meléndez Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages International Journal of Molecular Sciences CATB HIV MDM CB2R NF-κB Nrf2 |
| title | Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages |
| title_full | Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages |
| title_fullStr | Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages |
| title_full_unstemmed | Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages |
| title_short | Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages |
| title_sort | quantitative proteomics reveal that cb2r agonist jwh 133 downregulates nf κb activation oxidative stress and lysosomal exocytosis from hiv infected macrophages |
| topic | CATB HIV MDM CB2R NF-κB Nrf2 |
| url | https://www.mdpi.com/1422-0067/25/6/3246 |
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