Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity
Microglia, the brain resident immune cells, play prominent roles in immune surveillance, tissue repair and neural regeneration. Despite these pro-survival actions, the relevance of these cells in the progression of several neuropathologies has been established. In the context of manganese (Mn) overe...
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todo:paper_03064522_v393_n_p206_PorteAlcon2023-10-03T15:22:29Z Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity Porte Alcon, S. Gorojod, R.M. Kotler, M.L. lysosomes, regulated necrosis manganese Manganism microglia parthanatos cathepsin D manganese nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1 reactive oxygen metabolite manganese animal cell apoptosis Article cell death cell disruption cell structure cell viability DNA damage genotoxicity human human cell lysosome microglia MTT assay nonhuman priority journal signal transduction animal cell death cell survival drug effect metabolism microglia mitochondrion mouse necrosis Animals Apoptosis Cell Death Cell Survival Lysosomes Manganese Mice Microglia Mitochondria Necrosis Reactive Oxygen Species Microglia, the brain resident immune cells, play prominent roles in immune surveillance, tissue repair and neural regeneration. Despite these pro-survival actions, the relevance of these cells in the progression of several neuropathologies has been established. In the context of manganese (Mn) overexposure, it has been proposed that microglial activation contributes to enhance the neurotoxicity. However, the occurrence of a direct cytotoxic effect of Mn on microglial cells remains controversial. In the present work, we investigated the potential vulnerability of immortalized mouse microglial cells (BV-2) toward Mn 2+ , focusing on the signaling pathways involved in cell death. Evidence obtained showed that Mn 2+ induces a decrease in cell viability which is associated with reactive oxygen species (ROS) generation. In this report we demonstrated, for the first time, that Mn 2+ triggers regulated necrosis (RN) in BV-2 cells involving two central mechanisms: parthanatos and lysosomal disruption. The occurrence of parthanatos is supported by several cellular and molecular events: (i) DNA damage; (ii) AIF translocation from mitochondria to the nucleus; (iii) mitochondrial membrane permeabilization; and (iv) PARP1-dependent cell death. On the other hand, Mn 2+ induces lysosomal membrane permeabilization (LMP) and cathepsin D (CatD) release into the cytosol supporting the lysosomal disruption. Pre-incubation with CatB and D inhibitors partially prevented the Mn 2+ -induced cell viability decrease. Altogether these events point to lysosomes as players in the execution of RN. In summary, our results suggest that microglial cells could be direct targets of Mn 2+ damage. In this scenario, Mn 2+ triggers cell death involving RN pathways. © 2018 IBRO JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_03064522_v393_n_p206_PorteAlcon |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
lysosomes, regulated necrosis manganese Manganism microglia parthanatos cathepsin D manganese nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1 reactive oxygen metabolite manganese animal cell apoptosis Article cell death cell disruption cell structure cell viability DNA damage genotoxicity human human cell lysosome microglia MTT assay nonhuman priority journal signal transduction animal cell death cell survival drug effect metabolism microglia mitochondrion mouse necrosis Animals Apoptosis Cell Death Cell Survival Lysosomes Manganese Mice Microglia Mitochondria Necrosis Reactive Oxygen Species |
| spellingShingle |
lysosomes, regulated necrosis manganese Manganism microglia parthanatos cathepsin D manganese nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1 reactive oxygen metabolite manganese animal cell apoptosis Article cell death cell disruption cell structure cell viability DNA damage genotoxicity human human cell lysosome microglia MTT assay nonhuman priority journal signal transduction animal cell death cell survival drug effect metabolism microglia mitochondrion mouse necrosis Animals Apoptosis Cell Death Cell Survival Lysosomes Manganese Mice Microglia Mitochondria Necrosis Reactive Oxygen Species Porte Alcon, S. Gorojod, R.M. Kotler, M.L. Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity |
| topic_facet |
lysosomes, regulated necrosis manganese Manganism microglia parthanatos cathepsin D manganese nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1 reactive oxygen metabolite manganese animal cell apoptosis Article cell death cell disruption cell structure cell viability DNA damage genotoxicity human human cell lysosome microglia MTT assay nonhuman priority journal signal transduction animal cell death cell survival drug effect metabolism microglia mitochondrion mouse necrosis Animals Apoptosis Cell Death Cell Survival Lysosomes Manganese Mice Microglia Mitochondria Necrosis Reactive Oxygen Species |
| description |
Microglia, the brain resident immune cells, play prominent roles in immune surveillance, tissue repair and neural regeneration. Despite these pro-survival actions, the relevance of these cells in the progression of several neuropathologies has been established. In the context of manganese (Mn) overexposure, it has been proposed that microglial activation contributes to enhance the neurotoxicity. However, the occurrence of a direct cytotoxic effect of Mn on microglial cells remains controversial. In the present work, we investigated the potential vulnerability of immortalized mouse microglial cells (BV-2) toward Mn 2+ , focusing on the signaling pathways involved in cell death. Evidence obtained showed that Mn 2+ induces a decrease in cell viability which is associated with reactive oxygen species (ROS) generation. In this report we demonstrated, for the first time, that Mn 2+ triggers regulated necrosis (RN) in BV-2 cells involving two central mechanisms: parthanatos and lysosomal disruption. The occurrence of parthanatos is supported by several cellular and molecular events: (i) DNA damage; (ii) AIF translocation from mitochondria to the nucleus; (iii) mitochondrial membrane permeabilization; and (iv) PARP1-dependent cell death. On the other hand, Mn 2+ induces lysosomal membrane permeabilization (LMP) and cathepsin D (CatD) release into the cytosol supporting the lysosomal disruption. Pre-incubation with CatB and D inhibitors partially prevented the Mn 2+ -induced cell viability decrease. Altogether these events point to lysosomes as players in the execution of RN. In summary, our results suggest that microglial cells could be direct targets of Mn 2+ damage. In this scenario, Mn 2+ triggers cell death involving RN pathways. © 2018 IBRO |
| format |
JOUR |
| author |
Porte Alcon, S. Gorojod, R.M. Kotler, M.L. |
| author_facet |
Porte Alcon, S. Gorojod, R.M. Kotler, M.L. |
| author_sort |
Porte Alcon, S. |
| title |
Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity |
| title_short |
Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity |
| title_full |
Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity |
| title_fullStr |
Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity |
| title_full_unstemmed |
Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity |
| title_sort |
regulated necrosis orchestrates microglial cell death in manganese-induced toxicity |
| url |
http://hdl.handle.net/20.500.12110/paper_03064522_v393_n_p206_PorteAlcon |
| work_keys_str_mv |
AT portealcons regulatednecrosisorchestratesmicroglialcelldeathinmanganeseinducedtoxicity AT gorojodrm regulatednecrosisorchestratesmicroglialcelldeathinmanganeseinducedtoxicity AT kotlerml regulatednecrosisorchestratesmicroglialcelldeathinmanganeseinducedtoxicity |
| _version_ |
1807321668656300032 |