Self-extracellular RNA promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals

Abstract Objective Astrocytes participate in the local innate immune response of the central nervous system. In response to stress such as ischemia, activated cells release endogenous factors known as damage-associated molecular patterns (DAMPs). Self-extracellular RNA (eRNA) is such a ubiquitous al...

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Autores principales:	Silvia Fischer, Emil Nasyrov, Monika Brosien, Klaus T. Preissner, Hugo H. Marti, Reiner Kunze
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Extracellular RNA Astrocyte Inflammation Stroke Ischemia/reperfusion PAMP Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/0caa6a0917ab42cbacfdd3aca7802f56
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spelling	oai:doaj.org-article:0caa6a0917ab42cbacfdd3aca7802f562021-11-08T11:14:22ZSelf-extracellular RNA promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals10.1186/s12974-021-02286-w1742-2094https://doaj.org/article/0caa6a0917ab42cbacfdd3aca7802f562021-11-01T00:00:00Zhttps://doi.org/10.1186/s12974-021-02286-whttps://doaj.org/toc/1742-2094Abstract Objective Astrocytes participate in the local innate immune response of the central nervous system. In response to stress such as ischemia, activated cells release endogenous factors known as damage-associated molecular patterns (DAMPs). Self-extracellular RNA (eRNA) is such a ubiquitous alarm signal. However, it is unclear whether eRNA is involved in the early acute phase of cerebral ischemia and is sufficient to sensitize astrocytes towards a DAMP or PAMP (pathogen-associated molecular pattern) reaction. Methods Pro-inflammatory activation upon eRNA stimulation was characterized in primary murine astrocyte cultures. In vivo, an experimental stroke model was used to localize and quantify eRNA in murine brain sections. Using primary cortical neurons and the mouse hippocampal neuronal cell line HT-22, neuronal RNA release upon stress conditions related to cerebral hypoxia/ischemia was analyzed. Results While low-dose eRNA alone did not promote pro-inflammatory activation of astrocytes in culture, it strongly enhanced the expression of pro-inflammatory cytokines in the presence of either Pam2CSK4, a synthetic PAMP molecule that mimics bacterial infection, or high mobility group box 1 (HMGB1), a prominent DAMP. Synergism of eRNA/Pam2CSK4 and eRNA/HMGB1 was prevented by blockage of the astroglial toll-like receptor (TLR)-2. Inhibition of NF-κB- and mitogen-activated protein kinase-dependent signaling pathways hampered eRNA/Pam2CSK4-mediated pro-inflammatory activation of astrocytes. In vivo, the amount of non-nuclear, presumably extracellular ribosomal RNA in close proximity to neurons significantly accumulated across the infarct core and peri-infarct areas that was accompanied by transcriptional up-regulation of various pro-inflammatory factors. Accordingly, the exposure of neurons to hypoxic/ischemic stress in vitro resulted in the release of eRNA, partly mediated by active cellular processes dependent on the cytosolic calcium level. Conclusion The DAMP signal eRNA can sensitize astrocytes as active players in cerebral innate immunity towards exogenous and endogenous activators of inflammation (PAMPs and DAMPs) in a synergistic manner via TLR2-NF-κB-dependent signaling mechanisms. These findings provide new insights into the pathogenesis of ischemic stroke and other inflammatory neurological disorders. Further studies will clarify whether administration of RNase in vivo may serve as an effective treatment for inflammatory brain pathologies.Silvia FischerEmil NasyrovMonika BrosienKlaus T. PreissnerHugo H. MartiReiner KunzeBMCarticleExtracellular RNAAstrocyteInflammationStrokeIschemia/reperfusionPAMPNeurology. Diseases of the nervous systemRC346-429ENJournal of Neuroinflammation, Vol 18, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Extracellular RNA Astrocyte Inflammation Stroke Ischemia/reperfusion PAMP Neurology. Diseases of the nervous system RC346-429
spellingShingle	Extracellular RNA Astrocyte Inflammation Stroke Ischemia/reperfusion PAMP Neurology. Diseases of the nervous system RC346-429 Silvia Fischer Emil Nasyrov Monika Brosien Klaus T. Preissner Hugo H. Marti Reiner Kunze Self-extracellular RNA promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals
description	Abstract Objective Astrocytes participate in the local innate immune response of the central nervous system. In response to stress such as ischemia, activated cells release endogenous factors known as damage-associated molecular patterns (DAMPs). Self-extracellular RNA (eRNA) is such a ubiquitous alarm signal. However, it is unclear whether eRNA is involved in the early acute phase of cerebral ischemia and is sufficient to sensitize astrocytes towards a DAMP or PAMP (pathogen-associated molecular pattern) reaction. Methods Pro-inflammatory activation upon eRNA stimulation was characterized in primary murine astrocyte cultures. In vivo, an experimental stroke model was used to localize and quantify eRNA in murine brain sections. Using primary cortical neurons and the mouse hippocampal neuronal cell line HT-22, neuronal RNA release upon stress conditions related to cerebral hypoxia/ischemia was analyzed. Results While low-dose eRNA alone did not promote pro-inflammatory activation of astrocytes in culture, it strongly enhanced the expression of pro-inflammatory cytokines in the presence of either Pam2CSK4, a synthetic PAMP molecule that mimics bacterial infection, or high mobility group box 1 (HMGB1), a prominent DAMP. Synergism of eRNA/Pam2CSK4 and eRNA/HMGB1 was prevented by blockage of the astroglial toll-like receptor (TLR)-2. Inhibition of NF-κB- and mitogen-activated protein kinase-dependent signaling pathways hampered eRNA/Pam2CSK4-mediated pro-inflammatory activation of astrocytes. In vivo, the amount of non-nuclear, presumably extracellular ribosomal RNA in close proximity to neurons significantly accumulated across the infarct core and peri-infarct areas that was accompanied by transcriptional up-regulation of various pro-inflammatory factors. Accordingly, the exposure of neurons to hypoxic/ischemic stress in vitro resulted in the release of eRNA, partly mediated by active cellular processes dependent on the cytosolic calcium level. Conclusion The DAMP signal eRNA can sensitize astrocytes as active players in cerebral innate immunity towards exogenous and endogenous activators of inflammation (PAMPs and DAMPs) in a synergistic manner via TLR2-NF-κB-dependent signaling mechanisms. These findings provide new insights into the pathogenesis of ischemic stroke and other inflammatory neurological disorders. Further studies will clarify whether administration of RNase in vivo may serve as an effective treatment for inflammatory brain pathologies.
format	article
author	Silvia Fischer Emil Nasyrov Monika Brosien Klaus T. Preissner Hugo H. Marti Reiner Kunze
author_facet	Silvia Fischer Emil Nasyrov Monika Brosien Klaus T. Preissner Hugo H. Marti Reiner Kunze
author_sort	Silvia Fischer
title	Self-extracellular RNA promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals
title_short	Self-extracellular RNA promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals
title_full	Self-extracellular RNA promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals
title_fullStr	Self-extracellular RNA promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals
title_full_unstemmed	Self-extracellular RNA promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals
title_sort	self-extracellular rna promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals
publisher	BMC
publishDate	2021
url	https://doaj.org/article/0caa6a0917ab42cbacfdd3aca7802f56
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Self-extracellular RNA promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals

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