α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β1–42-stimulated murine astrocytes

Ebrahimi, Taraneh; Rust, Marcus Immanuel; Kaiser, Sarah; Slowik, Alexander; Beyer, Cordian; Koczulla, Andreas Rembert; Schulz, Jörg B.; Habib, Pardes; Bach, Jan-Philipp

doi:10.1186/s12974-018-1319-x

Cited by 56 publications

(41 citation statements)

References 67 publications

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“…and cation homeostasis, and cytoskeleton related processes (Table 3). Besides the expected oligodendrocyte compatible ones, the overrepresentation test indicated involvement of astrocyte and microglia related events such as glutamate metabolic process [23] and inflammatory response [24,25]. These data are consistent with the accepted view that CPZ induced oligodendrocyte loss is accompanied by expansion and activation of microglia and astrocytes [26].…”

Section: Plos Onesupporting

confidence: 88%

Proteomic changes during experimental de- and remyelination in the corpus callosum

et al. 2020

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Background In the cuprizone model of multiple sclerosis, de-and remyelination can be studied without major interference from the adaptive immune responses. Since previous proteomic studies did not focus on the corpus callosum, where cuprizone causes the most pronounced demyelination, we performed a bottom up proteomic analysis on this brain region. Methods Eight week-old mice treated with 0.2% cuprizone, for 4 weeks and controls (C) were sacrificed after termination of the treatment (4wD), and 2 (2dR) or 14 (2wR) days later. Homogenates of dissected corpus callosum were analysed by quantitative proteomics. For data processing, clustering, gene ontology analysis, and regulatory network prediction, we used Perseus, PANTHER and Ingenuity Pathway Analysis softwares, respectively. Results We identified 4886 unmodified, single-or multi phosphorylated and/or gycosylated (PTM) proteins. Out of them, 191 proteins were differentially regulated in at least one experimental group. We found 57 proteins specific for demyelination, 27 for early-and 57 for late remyelinationwhile 36 proteins were affected in two, and 23 proteins in all three groups. Phosphorylation represented 92% of the post translational modifications among differentially regulated modified (PTM) proteins with decreased level, while it was only 30% of the PTM proteins with increased level. Gene ontology analysis could not classify the demyelination specific proteins into any biological process category, while allocated the remyelination specific ones to nervous system development and myelination as the most specific subcategory. We also identified a protein network in experimental remyelination, and the gene

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Section: Plos Onesupporting

confidence: 88%

Proteomic changes during experimental de- and remyelination in the corpus callosum

et al. 2020

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“…We could not rule out the role of astroglia in LPS-induced sepsis-associated neurodegeneration. MCC950 also displayed the potency to repress astroglial NLRP3 inflammasome [91]. These findings highlight the promising application of NLRP3-IL-1β signaling inhibition in various neurodegenerative disorders.…”

Section: Roles Of Il-1β In Neuroinflammationmentioning

confidence: 69%

“…Moreover, astroglia can express NLRP3 inflammasome and IL-1β under certain conditions, such as in SOD1 mouse model of amyotrophic lateral sclerosis (ALS) and human sporadic ALS patients, and amyloid β 1-42 -stimulated murine astrocytes [90,91]. We could not rule out the role of astroglia in LPS-induced sepsis-associated neurodegeneration.…”

Section: Roles Of Il-1β In Neuroinflammationmentioning

confidence: 92%

A novel role of NLRP3-generated IL-1β in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: implications for sepsis-associated neurodegeneration

Zhao

Wang

Zhou

et al. 2020

J Neuroinflammation

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Background: Sepsis-associated acute brain inflammation, if unresolved, may cause chronic neuroinflammation and resultant neurodegenerative diseases. However, little is known how the transition from acute to chronic neuroinflammation, which is critical for the following progressive neurodegeneration, occurs in sepsis. The goal of this study was to investigate potential immune factors regulating the transition process using a widely used endotoxemia LPS mouse model. This model shows distinct acute and chronic phases of neuroinflammation and recapitulates many cardinal features of Parkinson's disease, thus, providing a unique opportunity for studying phase transition of neuroinflammation.Methods: C57BL/6 J, NLRP3 −/− , and IL-1R1 −/− mice were employed. Mild and severe endotoxemia were produced by LPS ip injection at 1 or 5 mg/kg. Neuroinflammation in vitro and in vivo was assessed with proinflammatory cytokine expression by qPCR or ELISA and microglial activation by immunohistochemical analysis. Neurodegeneration was measured by manual and stereological counts of nigral dopaminergic neurons and immunohistochemical analysis of protein nitrosylation and α-synuclein phosphorylation. Results: LPS-elicited initial increases in mouse brain mRNA levels of TNFα, IL-6, IL-1β, and MCP-1, and nigral microglial activation were not dose-related. By contrast, the delayed increase in brain mature IL-1β levels was dependent on LPS doses and protracted nigral microglial activation was only observed in high dose of LPS-treated mice. LPS-elicited increase in brain mature IL-1β but not IL-1α level was NLRP3-dependent. After high dose LPS treatment, deficiency of NLRP3 or IL-1R1 did not prevent the initiation of acute neuroinflammation but abolished chronic neuroinflammation. Genetic or pharmacological inhibition of the NLRP3-IL-1β axis repressed LPS-stimulated upregulation of chronic neuroinflammatory mediators including MHC-II, NOX2, and Mac1, and protected dopaminergic neurons. Ten months after LPS-elicited severe endotoxemia, nigral persisted microglial activation, elevated nitrosylated proteins and phosphorylated α-synuclein, and significant neuronal degeneration developed in wild-type mice but not in NLRP3 −/− or IL-1R1 −/− mice.

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“…In our experiments, however, Aβ 1-42 was applied together with BzATP for only 30 min, which is probably not enough time for an efficient induction of gene expression and protein synthesis. Other studies found that fibrillar and monomeric Aβ 1-42 can activate the NLRP3 inflammasome, thereby inducing the release of mature IL-1β [ 29 , 38 , 84 , 85 ]. This probably depends on the internalization of Aβ 1-42 fibrils via the scavenger receptor CD36, followed by lysosomal rupture, a known signal of NLRP3 assembly [ 29 , 86 , 87 ].…”

Section: Discussionmentioning

confidence: 99%

Amyloid Beta Peptide (Aβ1-42) Reverses the Cholinergic Control of Monocytic IL-1β Release

Richter

Ogiemwonyi-Schaefer

Wilker

et al. 2020

JCM

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Amyloid-β peptide (Aβ1-42), the cleavage product of the evolutionary highly conserved amyloid precursor protein, presumably plays a pathogenic role in Alzheimer’s disease. Aβ1-42 can induce the secretion of the pro-inflammatory cytokine intereukin-1β (IL-1β) in immune cells within and out of the nervous system. Known interaction partners of Aβ1-42 are α7 nicotinic acetylcholine receptors (nAChRs). The physiological functions of Aβ1-42 are, however, not fully understood. Recently, we identified a cholinergic mechanism that controls monocytic release of IL-1β by canonical and non-canonical agonists of nAChRs containing subunits α7, α9, and/or α10. Here, we tested the hypothesis that Aβ1-42 modulates this inhibitory cholinergic mechanism. Lipopolysaccharide-primed monocytic U937 cells and human mononuclear leukocytes were stimulated with the P2X7 receptor agonist 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate triethylammonium salt (BzATP) in the presence or absence of nAChR agonists and Aβ1-42. IL-1β concentrations were measured in the supernatant. Aβ1-42 dose-dependently (IC50 = 2.54 µM) reversed the inhibitory effect of canonical and non-canonical nicotinic agonists on BzATP-mediated IL-1β-release by monocytic cells, whereas reverse Aβ42-1 was ineffective. In conclusion, we discovered a novel pro-inflammatory Aβ1-42 function that enables monocytic IL-1β release in the presence of nAChR agonists. These findings provide evidence for a novel physiological function of Aβ1-42 in the context of sterile systemic inflammation.

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α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β1–42-stimulated murine astrocytes

Cited by 56 publications

References 67 publications

Proteomic changes during experimental de- and remyelination in the corpus callosum

Proteomic changes during experimental de- and remyelination in the corpus callosum

A novel role of NLRP3-generated IL-1β in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: implications for sepsis-associated neurodegeneration

Amyloid Beta Peptide (Aβ1-42) Reverses the Cholinergic Control of Monocytic IL-1β Release

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