Inflammatory response of microglia to prions is controlled by sialylation of PrPSc
Abstract Neuroinflammation is recognized as one of the obligatory pathogenic features of neurodegenerative diseases including Alzheimer’s, Parkinson’s or prion diseases. In prion diseases, space and time correlations between deposition of disease-associated, pathogenic form of the prion protein or P...
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oai:doaj.org-article:73bae15539c04cfe9bbcf492a6065dd62021-12-02T15:08:24ZInflammatory response of microglia to prions is controlled by sialylation of PrPSc10.1038/s41598-018-29720-z2045-2322https://doaj.org/article/73bae15539c04cfe9bbcf492a6065dd62018-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-29720-zhttps://doaj.org/toc/2045-2322Abstract Neuroinflammation is recognized as one of the obligatory pathogenic features of neurodegenerative diseases including Alzheimer’s, Parkinson’s or prion diseases. In prion diseases, space and time correlations between deposition of disease-associated, pathogenic form of the prion protein or PrPSc and microglial-mediated neuroinflammation has been established. Yet, it remains unclear whether activation of microglia is triggered directly by a contact with PrPSc, and what molecular features of PrPSc microglia sense and respond to that drive microglia to inflammatory states. The current study asked the questions whether PrPSc can directly trigger activation of microglia and whether the degree of microglia response depends on the nature of terminal carbohydrate groups on the surface of PrPSc particles. PrPSc was purified from brains of mice infected with mouse-adapted prion strain 22L or neuroblastoma N2a cells stably infected with 22L. BV2 microglial cells or primary microglia were cultured in the presence of purified 22L. We found that exposure of BV2 cells or primary microglia to purified PrPSc triggered proinflammatory responses characterized by an increase in the levels of TNFα, IL6, nitric oxide (NO) and expression of inducible Nitric Oxide Synthase (iNOS). Very similar patterns of inflammatory response were induced by PrPSc purified from mouse brains and neuroblastoma cells arguing that microglia response is independent of the source of PrPSc. To test whether the microglial response is mediated by carbohydrate epitopes on PrPSc surface, the levels of sialylation of PrPSc N-linked glycans was altered by treatment of purified PrPSc with neuraminidase. Partial cleavage of sialic acid residues was found to boost the inflammatory response of microglia to PrPSc. Moreover, transient degradation of Iκβα observed upon treatment with partially desialylated PrPSc suggests that canonical NFκB activation pathway is involved in inflammatory response. The current study is the first to demonstrate that PrPSc can directly trigger inflammatory response in microglia. In addition, this work provides direct evidence that the chemical nature of the carbohydrate groups on PrPSc surface is important for microglial activation.Saurabh SrivastavaElizaveta KatorchaNatallia MakaravaJames P. BarrettDavid J. LoaneIlia V. BaskakovNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-15 (2018) |
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Medicine R Science Q Saurabh Srivastava Elizaveta Katorcha Natallia Makarava James P. Barrett David J. Loane Ilia V. Baskakov Inflammatory response of microglia to prions is controlled by sialylation of PrPSc |
description |
Abstract Neuroinflammation is recognized as one of the obligatory pathogenic features of neurodegenerative diseases including Alzheimer’s, Parkinson’s or prion diseases. In prion diseases, space and time correlations between deposition of disease-associated, pathogenic form of the prion protein or PrPSc and microglial-mediated neuroinflammation has been established. Yet, it remains unclear whether activation of microglia is triggered directly by a contact with PrPSc, and what molecular features of PrPSc microglia sense and respond to that drive microglia to inflammatory states. The current study asked the questions whether PrPSc can directly trigger activation of microglia and whether the degree of microglia response depends on the nature of terminal carbohydrate groups on the surface of PrPSc particles. PrPSc was purified from brains of mice infected with mouse-adapted prion strain 22L or neuroblastoma N2a cells stably infected with 22L. BV2 microglial cells or primary microglia were cultured in the presence of purified 22L. We found that exposure of BV2 cells or primary microglia to purified PrPSc triggered proinflammatory responses characterized by an increase in the levels of TNFα, IL6, nitric oxide (NO) and expression of inducible Nitric Oxide Synthase (iNOS). Very similar patterns of inflammatory response were induced by PrPSc purified from mouse brains and neuroblastoma cells arguing that microglia response is independent of the source of PrPSc. To test whether the microglial response is mediated by carbohydrate epitopes on PrPSc surface, the levels of sialylation of PrPSc N-linked glycans was altered by treatment of purified PrPSc with neuraminidase. Partial cleavage of sialic acid residues was found to boost the inflammatory response of microglia to PrPSc. Moreover, transient degradation of Iκβα observed upon treatment with partially desialylated PrPSc suggests that canonical NFκB activation pathway is involved in inflammatory response. The current study is the first to demonstrate that PrPSc can directly trigger inflammatory response in microglia. In addition, this work provides direct evidence that the chemical nature of the carbohydrate groups on PrPSc surface is important for microglial activation. |
format |
article |
author |
Saurabh Srivastava Elizaveta Katorcha Natallia Makarava James P. Barrett David J. Loane Ilia V. Baskakov |
author_facet |
Saurabh Srivastava Elizaveta Katorcha Natallia Makarava James P. Barrett David J. Loane Ilia V. Baskakov |
author_sort |
Saurabh Srivastava |
title |
Inflammatory response of microglia to prions is controlled by sialylation of PrPSc |
title_short |
Inflammatory response of microglia to prions is controlled by sialylation of PrPSc |
title_full |
Inflammatory response of microglia to prions is controlled by sialylation of PrPSc |
title_fullStr |
Inflammatory response of microglia to prions is controlled by sialylation of PrPSc |
title_full_unstemmed |
Inflammatory response of microglia to prions is controlled by sialylation of PrPSc |
title_sort |
inflammatory response of microglia to prions is controlled by sialylation of prpsc |
publisher |
Nature Portfolio |
publishDate |
2018 |
url |
https://doaj.org/article/73bae15539c04cfe9bbcf492a6065dd6 |
work_keys_str_mv |
AT saurabhsrivastava inflammatoryresponseofmicrogliatoprionsiscontrolledbysialylationofprpsc AT elizavetakatorcha inflammatoryresponseofmicrogliatoprionsiscontrolledbysialylationofprpsc AT natalliamakarava inflammatoryresponseofmicrogliatoprionsiscontrolledbysialylationofprpsc AT jamespbarrett inflammatoryresponseofmicrogliatoprionsiscontrolledbysialylationofprpsc AT davidjloane inflammatoryresponseofmicrogliatoprionsiscontrolledbysialylationofprpsc AT iliavbaskakov inflammatoryresponseofmicrogliatoprionsiscontrolledbysialylationofprpsc |
_version_ |
1718388127841648640 |