Silica-coated magnetic nanoparticles activate microglia and induce neurotoxic d-serine secretion
Abstract Background Nanoparticles have been studied for brain imaging, diagnosis, and drug delivery owing to their versatile properties due to their small sizes. However, there are growing concerns that nanoparticles may exert toxic effects in the brain. In this study, we assessed direct nanotoxicit...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-08-01
|
| Series: | Particle and Fibre Toxicology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12989-021-00420-3 |
| _version_ | 1818596651660476416 |
|---|---|
| author | Tae Hwan Shin Da Yeon Lee Balachandran Manavalan Shaherin Basith Yun-Cheol Na Cheolho Yoon Hyeon-Seong Lee Man Jeong Paik Gwang Lee |
| author_facet | Tae Hwan Shin Da Yeon Lee Balachandran Manavalan Shaherin Basith Yun-Cheol Na Cheolho Yoon Hyeon-Seong Lee Man Jeong Paik Gwang Lee |
| author_sort | Tae Hwan Shin |
| collection | DOAJ |
| description | Abstract Background Nanoparticles have been studied for brain imaging, diagnosis, and drug delivery owing to their versatile properties due to their small sizes. However, there are growing concerns that nanoparticles may exert toxic effects in the brain. In this study, we assessed direct nanotoxicity on microglia, the resident macrophages of the central nervous system, and indirect toxicity on neuronal cells exerted by silica-coated magnetic nanoparticles containing rhodamine B isothiocyanate dye [MNPs@SiO2(RITC)]. Methods We investigated MNPs@SiO2(RITC)-induced biological changes in BV2 murine microglial cells via RNA-sequencing-based transcriptome analysis and gas chromatography-mass spectrometry-based intracellular and extracellular amino acid profiling. Morphological changes were analyzed by transmission electron microscopy. Indirect effects of MNPs@SiO2(RITC) on neuronal cells were assessed by Transwell-based coculture with MNPs@SiO2(RITC)-treated microglia. MNPs@SiO2(RITC)-induced biological changes in the mouse brain in vivo were examined by immunohistochemical analysis. Results BV2 murine microglial cells were morphologically activated and the expression of Iba1, an activation marker protein, was increased after MNPs@SiO2(RITC) treatment. Transmission electron microscopy analysis revealed lysosomal accumulation of MNPs@SiO2(RITC) and the formation of vesicle-like structures in MNPs@SiO2(RITC)-treated BV2 cells. The expression of several genes related to metabolism and inflammation were altered in 100 µg/ml MNPs@SiO2(RITC)-treated microglia when compared with that in non-treated (control) and 10 µg/ml MNPs@SiO2(RITC)-treated microglia. Combined transcriptome and amino acid profiling analyses revealed that the transport of serine family amino acids, including glycine, cysteine, and serine, was enhanced. However, only serine was increased in the growth medium of activated microglia; especially, excitotoxic D-serine secretion from primary rat microglia was the most strongly enhanced. Activated primary microglia reduced intracellular ATP levels and proteasome activity in cocultured neuronal cells, especially in primary cortical neurons, via D-serine secretion. Moreover, ubiquitinated proteins accumulated and inclusion bodies were increased in primary dopaminergic and cortical neurons cocultured with activated primary microglia. In vivo, MNPs@SiO2(RITC), D-serine, and ubiquitin aggresomes were distributed in the MNPs@SiO2(RITC)-treated mouse brain. Conclusions MNPs@SiO2(RITC)-induced activation of microglia triggers excitotoxicity in neurons via D-serine secretion, highlighting the importance of neurotoxicity mechanisms incurred by nanoparticle-induced microglial activation. |
| first_indexed | 2024-12-16T11:35:18Z |
| format | Article |
| id | doaj.art-87a311fc92e948ffb53b5438139e3e59 |
| institution | Directory Open Access Journal |
| issn | 1743-8977 |
| language | English |
| last_indexed | 2024-12-16T11:35:18Z |
| publishDate | 2021-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Particle and Fibre Toxicology |
| spelling | doaj.art-87a311fc92e948ffb53b5438139e3e592022-12-21T22:33:09ZengBMCParticle and Fibre Toxicology1743-89772021-08-0118111810.1186/s12989-021-00420-3Silica-coated magnetic nanoparticles activate microglia and induce neurotoxic d-serine secretionTae Hwan Shin0Da Yeon Lee1Balachandran Manavalan2Shaherin Basith3Yun-Cheol Na4Cheolho Yoon5Hyeon-Seong Lee6Man Jeong Paik7Gwang Lee8Department of Physiology, Ajou University School of MedicineDepartment of Physiology, Ajou University School of MedicineDepartment of Physiology, Ajou University School of MedicineDepartment of Physiology, Ajou University School of MedicineWestern Seoul Center, Korea Basic Science InstituteOchang Center, Korea Basic Science InstituteCollege of Pharmacy, Sunchon National UniversityCollege of Pharmacy, Sunchon National UniversityDepartment of Physiology, Ajou University School of MedicineAbstract Background Nanoparticles have been studied for brain imaging, diagnosis, and drug delivery owing to their versatile properties due to their small sizes. However, there are growing concerns that nanoparticles may exert toxic effects in the brain. In this study, we assessed direct nanotoxicity on microglia, the resident macrophages of the central nervous system, and indirect toxicity on neuronal cells exerted by silica-coated magnetic nanoparticles containing rhodamine B isothiocyanate dye [MNPs@SiO2(RITC)]. Methods We investigated MNPs@SiO2(RITC)-induced biological changes in BV2 murine microglial cells via RNA-sequencing-based transcriptome analysis and gas chromatography-mass spectrometry-based intracellular and extracellular amino acid profiling. Morphological changes were analyzed by transmission electron microscopy. Indirect effects of MNPs@SiO2(RITC) on neuronal cells were assessed by Transwell-based coculture with MNPs@SiO2(RITC)-treated microglia. MNPs@SiO2(RITC)-induced biological changes in the mouse brain in vivo were examined by immunohistochemical analysis. Results BV2 murine microglial cells were morphologically activated and the expression of Iba1, an activation marker protein, was increased after MNPs@SiO2(RITC) treatment. Transmission electron microscopy analysis revealed lysosomal accumulation of MNPs@SiO2(RITC) and the formation of vesicle-like structures in MNPs@SiO2(RITC)-treated BV2 cells. The expression of several genes related to metabolism and inflammation were altered in 100 µg/ml MNPs@SiO2(RITC)-treated microglia when compared with that in non-treated (control) and 10 µg/ml MNPs@SiO2(RITC)-treated microglia. Combined transcriptome and amino acid profiling analyses revealed that the transport of serine family amino acids, including glycine, cysteine, and serine, was enhanced. However, only serine was increased in the growth medium of activated microglia; especially, excitotoxic D-serine secretion from primary rat microglia was the most strongly enhanced. Activated primary microglia reduced intracellular ATP levels and proteasome activity in cocultured neuronal cells, especially in primary cortical neurons, via D-serine secretion. Moreover, ubiquitinated proteins accumulated and inclusion bodies were increased in primary dopaminergic and cortical neurons cocultured with activated primary microglia. In vivo, MNPs@SiO2(RITC), D-serine, and ubiquitin aggresomes were distributed in the MNPs@SiO2(RITC)-treated mouse brain. Conclusions MNPs@SiO2(RITC)-induced activation of microglia triggers excitotoxicity in neurons via D-serine secretion, highlighting the importance of neurotoxicity mechanisms incurred by nanoparticle-induced microglial activation.https://doi.org/10.1186/s12989-021-00420-3Silica-coated magnetic nanoparticlesNanotoxicityMicrogliaExcitotoxicityInclusion body |
| spellingShingle | Tae Hwan Shin Da Yeon Lee Balachandran Manavalan Shaherin Basith Yun-Cheol Na Cheolho Yoon Hyeon-Seong Lee Man Jeong Paik Gwang Lee Silica-coated magnetic nanoparticles activate microglia and induce neurotoxic d-serine secretion Particle and Fibre Toxicology Silica-coated magnetic nanoparticles Nanotoxicity Microglia Excitotoxicity Inclusion body |
| title | Silica-coated magnetic nanoparticles activate microglia and induce neurotoxic d-serine secretion |
| title_full | Silica-coated magnetic nanoparticles activate microglia and induce neurotoxic d-serine secretion |
| title_fullStr | Silica-coated magnetic nanoparticles activate microglia and induce neurotoxic d-serine secretion |
| title_full_unstemmed | Silica-coated magnetic nanoparticles activate microglia and induce neurotoxic d-serine secretion |
| title_short | Silica-coated magnetic nanoparticles activate microglia and induce neurotoxic d-serine secretion |
| title_sort | silica coated magnetic nanoparticles activate microglia and induce neurotoxic d serine secretion |
| topic | Silica-coated magnetic nanoparticles Nanotoxicity Microglia Excitotoxicity Inclusion body |
| url | https://doi.org/10.1186/s12989-021-00420-3 |
| work_keys_str_mv | AT taehwanshin silicacoatedmagneticnanoparticlesactivatemicrogliaandinduceneurotoxicdserinesecretion AT dayeonlee silicacoatedmagneticnanoparticlesactivatemicrogliaandinduceneurotoxicdserinesecretion AT balachandranmanavalan silicacoatedmagneticnanoparticlesactivatemicrogliaandinduceneurotoxicdserinesecretion AT shaherinbasith silicacoatedmagneticnanoparticlesactivatemicrogliaandinduceneurotoxicdserinesecretion AT yuncheolna silicacoatedmagneticnanoparticlesactivatemicrogliaandinduceneurotoxicdserinesecretion AT cheolhoyoon silicacoatedmagneticnanoparticlesactivatemicrogliaandinduceneurotoxicdserinesecretion AT hyeonseonglee silicacoatedmagneticnanoparticlesactivatemicrogliaandinduceneurotoxicdserinesecretion AT manjeongpaik silicacoatedmagneticnanoparticlesactivatemicrogliaandinduceneurotoxicdserinesecretion AT gwanglee silicacoatedmagneticnanoparticlesactivatemicrogliaandinduceneurotoxicdserinesecretion |