Alcohol and HIV-Derived Hepatocyte Apoptotic Bodies Induce Hepatic Stellate Cell Activation
Recently, we found that both HIV and acetaldehyde, an alcohol metabolite, induce hepatocyte apoptosis, resulting in the release of large extracellular vesicles called apoptotic bodies (ABs). The engulfment of these hepatocyte ABs by hepatic stellate cells (HSC) leads to their profibrotic activation....
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-07-01
|
| Series: | Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-7737/11/7/1059 |
| _version_ | 1797440764391718912 |
|---|---|
| author | Moses New-Aaron Raghubendra Singh Dagur Siva Sankar Koganti Murali Ganesan Weimin Wang Edward Makarov Mojisola Ogunnaike Kusum K. Kharbanda Larisa Y. Poluektova Natalia A. Osna |
| author_facet | Moses New-Aaron Raghubendra Singh Dagur Siva Sankar Koganti Murali Ganesan Weimin Wang Edward Makarov Mojisola Ogunnaike Kusum K. Kharbanda Larisa Y. Poluektova Natalia A. Osna |
| author_sort | Moses New-Aaron |
| collection | DOAJ |
| description | Recently, we found that both HIV and acetaldehyde, an alcohol metabolite, induce hepatocyte apoptosis, resulting in the release of large extracellular vesicles called apoptotic bodies (ABs). The engulfment of these hepatocyte ABs by hepatic stellate cells (HSC) leads to their profibrotic activation. This study aims to establish the mechanisms of HSC activation after engulfment of ABs from acetaldehyde and HIV-exposed hepatocytes (AB<sub>AGS+HIV</sub>). In vitro experiments were performed on Huh7.5-CYP (RLW) cells to generate hepatocyte ABs and LX2 cells were used as HSC. To generate ABs, RLW cells were pretreated for 24 h with acetaldehyde, then exposed overnight to HIV1<sub>ADA</sub> and to acetaldehyde for 96 h. Thereafter, ABs were isolated from cell suspension by a differential centrifugation method and incubated with LX2 cells (3:1 ratio) for profibrotic genes and protein analyses. We found that HSC internalized ABs via the tyrosine kinase receptor, Axl. While the HIV gag RNA/HIV proteins accumulated in ABs elicited no productive infection in LX2 and immune cells, they triggered ROS and IL6 generation, which, in turn, activated profibrotic genes via the JNK-ERK1/2 and JAK-STAT3 pathways. Similarly, ongoing profibrotic activation was observed in immunodeficient NSG mice fed ethanol and injected with HIV-derived RLW ABs. We conclude that HSC activation by hepatocyte AB<sub>AGS+HIV</sub> engulfment is mediated by ROS-dependent JNK-ERK1/2 and IL6 triggering of JAK-STAT3 pathways. This can partially explain the mechanisms of liver fibrosis development frequently observed among alcohol abusing PLWH. |
| first_indexed | 2024-03-09T12:14:05Z |
| format | Article |
| id | doaj.art-a2c88a9ccab347dcbd734c245c0ed0bc |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-09T12:14:05Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-a2c88a9ccab347dcbd734c245c0ed0bc2023-11-30T22:49:27ZengMDPI AGBiology2079-77372022-07-01117105910.3390/biology11071059Alcohol and HIV-Derived Hepatocyte Apoptotic Bodies Induce Hepatic Stellate Cell ActivationMoses New-Aaron0Raghubendra Singh Dagur1Siva Sankar Koganti2Murali Ganesan3Weimin Wang4Edward Makarov5Mojisola Ogunnaike6Kusum K. Kharbanda7Larisa Y. Poluektova8Natalia A. Osna9Department of Environmental Health, Occupational Health and Toxicology, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USAResearch Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USAResearch Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USAResearch Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USADepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USADepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USAResearch Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USAResearch Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USADepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USADepartment of Environmental Health, Occupational Health and Toxicology, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USARecently, we found that both HIV and acetaldehyde, an alcohol metabolite, induce hepatocyte apoptosis, resulting in the release of large extracellular vesicles called apoptotic bodies (ABs). The engulfment of these hepatocyte ABs by hepatic stellate cells (HSC) leads to their profibrotic activation. This study aims to establish the mechanisms of HSC activation after engulfment of ABs from acetaldehyde and HIV-exposed hepatocytes (AB<sub>AGS+HIV</sub>). In vitro experiments were performed on Huh7.5-CYP (RLW) cells to generate hepatocyte ABs and LX2 cells were used as HSC. To generate ABs, RLW cells were pretreated for 24 h with acetaldehyde, then exposed overnight to HIV1<sub>ADA</sub> and to acetaldehyde for 96 h. Thereafter, ABs were isolated from cell suspension by a differential centrifugation method and incubated with LX2 cells (3:1 ratio) for profibrotic genes and protein analyses. We found that HSC internalized ABs via the tyrosine kinase receptor, Axl. While the HIV gag RNA/HIV proteins accumulated in ABs elicited no productive infection in LX2 and immune cells, they triggered ROS and IL6 generation, which, in turn, activated profibrotic genes via the JNK-ERK1/2 and JAK-STAT3 pathways. Similarly, ongoing profibrotic activation was observed in immunodeficient NSG mice fed ethanol and injected with HIV-derived RLW ABs. We conclude that HSC activation by hepatocyte AB<sub>AGS+HIV</sub> engulfment is mediated by ROS-dependent JNK-ERK1/2 and IL6 triggering of JAK-STAT3 pathways. This can partially explain the mechanisms of liver fibrosis development frequently observed among alcohol abusing PLWH.https://www.mdpi.com/2079-7737/11/7/1059hepatocytesapoptotic bodieshepatic stellate cellsJNK-ERK1/2reactive oxygen speciesJAK-STAT3 |
| spellingShingle | Moses New-Aaron Raghubendra Singh Dagur Siva Sankar Koganti Murali Ganesan Weimin Wang Edward Makarov Mojisola Ogunnaike Kusum K. Kharbanda Larisa Y. Poluektova Natalia A. Osna Alcohol and HIV-Derived Hepatocyte Apoptotic Bodies Induce Hepatic Stellate Cell Activation Biology hepatocytes apoptotic bodies hepatic stellate cells JNK-ERK1/2 reactive oxygen species JAK-STAT3 |
| title | Alcohol and HIV-Derived Hepatocyte Apoptotic Bodies Induce Hepatic Stellate Cell Activation |
| title_full | Alcohol and HIV-Derived Hepatocyte Apoptotic Bodies Induce Hepatic Stellate Cell Activation |
| title_fullStr | Alcohol and HIV-Derived Hepatocyte Apoptotic Bodies Induce Hepatic Stellate Cell Activation |
| title_full_unstemmed | Alcohol and HIV-Derived Hepatocyte Apoptotic Bodies Induce Hepatic Stellate Cell Activation |
| title_short | Alcohol and HIV-Derived Hepatocyte Apoptotic Bodies Induce Hepatic Stellate Cell Activation |
| title_sort | alcohol and hiv derived hepatocyte apoptotic bodies induce hepatic stellate cell activation |
| topic | hepatocytes apoptotic bodies hepatic stellate cells JNK-ERK1/2 reactive oxygen species JAK-STAT3 |
| url | https://www.mdpi.com/2079-7737/11/7/1059 |
| work_keys_str_mv | AT mosesnewaaron alcoholandhivderivedhepatocyteapoptoticbodiesinducehepaticstellatecellactivation AT raghubendrasinghdagur alcoholandhivderivedhepatocyteapoptoticbodiesinducehepaticstellatecellactivation AT sivasankarkoganti alcoholandhivderivedhepatocyteapoptoticbodiesinducehepaticstellatecellactivation AT muraliganesan alcoholandhivderivedhepatocyteapoptoticbodiesinducehepaticstellatecellactivation AT weiminwang alcoholandhivderivedhepatocyteapoptoticbodiesinducehepaticstellatecellactivation AT edwardmakarov alcoholandhivderivedhepatocyteapoptoticbodiesinducehepaticstellatecellactivation AT mojisolaogunnaike alcoholandhivderivedhepatocyteapoptoticbodiesinducehepaticstellatecellactivation AT kusumkkharbanda alcoholandhivderivedhepatocyteapoptoticbodiesinducehepaticstellatecellactivation AT larisaypoluektova alcoholandhivderivedhepatocyteapoptoticbodiesinducehepaticstellatecellactivation AT nataliaaosna alcoholandhivderivedhepatocyteapoptoticbodiesinducehepaticstellatecellactivation |