Disease-associated amyloid and misfolded protein aggregates activate the inflammasome

Masters, Seth L.; O’Neill, Luke A.J.

doi:10.1016/j.molmed.2011.01.005

Cited by 126 publications

(102 citation statements)

References 75 publications

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“…2), presumably in a NF-κB-dependent manner. The NLRP3 inflammasome is tightly regulated and its activation requires two signals (Masters and O'Neill, 2011). NF-κB is an essential priming signal that promotes the expression of inflammasome components as well as that of the substrates IL-1β and IL-18 (Bauernfeind et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…NF-κB is an essential priming signal that promotes the expression of inflammasome components as well as that of the substrates IL-1β and IL-18 (Bauernfeind et al, 2009). Aβ oligomers and other misfolded proteins can serve as the second, activating signal that triggers inflammasome assembly (Masters and O'Neill, 2011). By preventing NF-κB activation, vinpocetine inhibits the expression of downstream pathways.…”

Section: Discussionmentioning

confidence: 99%

“…The NLRP3 inflammasome is a critical cellular apparatus for the detection of noxious stimuli, including Aβ, and the subsequent production of mature pro-inflammatory cytokines to defend against cellular insults (Halle et al, 2008;Masters and O'Neill, 2011). NF-κB has been proposed as a prerequisite priming mechanism for inflammasome activation (Bauernfeind et al, 2009;Segovia et al, 2012).…”

Section: Vinpocetine Reduced the Expression Of Nlrp3-related Genes Anmentioning

confidence: 99%

“…A host of diverse molecules have been identified as activation signals, including pathogen-associated molecular patterns (PAMPs) such as pore-forming toxins, environmental irritants, dangerassociated molecular patterns (DAMPs) such as ATP, crystals, and proteins such as Aβ (Di Virgilio. 2013;Masters and O'Neill. 2011;Tschopp and Schroder.…”

Section: Introductionmentioning

confidence: 99%

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Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

Liu

Wang

et al. 2014

Experimental Eye Research

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Chronic inflammation is a key pathogenic process in age-related macular degeneration (AMD). Amyloid-beta (Aβ) is a constituent of AMD drusen and promotes the activation of NLRP3 inflammasome which facilitates the production of cytokines. We investigated the role of transcription factor NF-κB in the activation of inflammasome in the RPE and the effect of vinpocetine, a dietary supplement with inhibitory effect on NF-κB. ARPE19/NF-κB-luciferase reporter cells treated with Aβ demonstrated enhanced NF-κB activation that was significantly suppressed by vinpocetine. Intraperitoneal injection of vinpocetine (15 mg/kg) inhibited NF-κB nuclear translocation and reduced the expression and activation of NLRP3, caspase-1, IL-1β, IL-18, and TNF-α in the RPE of adult rats that received intraocular Aβ, as measured by retinal immunohistochemistry and Western blot. Cytokine level in the vitreous was assayed using multiplex suspension arrays and revealed significantly lower concentration of MIP-3α, IL-6, IL-1α, IL-1β, IL-18, and TNF-α in vinpocetine treated animals. These results suggest that the NF-κB pathway is activated by Aβ in the RPE and signals the priming of NLRP3 inflammasome and the expression of pro-inflammatory cytokines including the inflammasome substrates IL-1β and IL-18. NF-κB inhibition may be an effective approach to stem the chronic inflammatory milieu that underlies the development of AMD. Vinpocetine is a potentially useful anti-inflammatory agent that is well-tolerated in long term use.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Vinpocetine Reduced the Expression Of Nlrp3-related Genes Anmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

Liu

Wang

et al. 2014

Experimental Eye Research

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“…The activated UPR was enhanced in neurons with a diffuse pattern of phosphorylated tau [128], thus, suggesting that the UPR activation requires tau but precedes formation of neurofibrillary tau tangles. Microglia and infiltrating mononuclear phagocytes are recruited to amyloid  plaques, become activated and phagocytose amyloid  leading to activation of the NLRP3 inflammasome and production of pro-inflammatory cytokines, specifically IL-1 [130][131][132][133][134]. AD patients and rodent models showed increased IL-1 expression in microglia isolated from amyloid  plaques and increased CSF levels of IL-1 [135].…”

Section: Pdmentioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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Regulation of interleukin‐1 beta secretion from macrophages via modulation of potassium ion (K⁺) channel activity

et al. 2019

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A causal relationship exists between macrophage cholesterol levels and inflammation, for example, Interleukin‐1β (IL‐1β) secretion. A decrease in intracellular K+ is essential for inflammasome activation/IL‐1β secretion and, herein, we examined the hypothesis that cellular cholesterol affects K+‐channel activity and K+‐efflux using mouse peritoneal macrophages (MPMs) and human/THP1 macrophages. An increase in cellular cholesterol led to a significant increase in K+ currents (> 350% in both MPM and THP1). Enhancing cholesterol efflux returned K+ currents back to basal levels with corresponding increase in intracellular K+ (11.2–14.5%) and reduced IL‐1β secretion (32–62%). These data demonstrate a novel mechanism by which cellular cholesterol modulates inflammation/inflammasome via regulation of K+‐channel activity and intracellular K+ levels. Attenuation of IL‐1β secretion by Nateglinide/Repaglinide further suggests involvement of Kir6 channels.

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Disease-associated amyloid and misfolded protein aggregates activate the inflammasome

Cited by 126 publications

References 75 publications

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

Regulation of interleukin‐1 beta secretion from macrophages via modulation of potassium ion (K⁺) channel activity

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Disease-associated amyloid and misfolded protein aggregates activate the inflammasome

Cited by 126 publications

References 75 publications

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

Regulation of interleukin‐1 beta secretion from macrophages via modulation of potassium ion (K+) channel activity

Contact Info

Product

Resources

About

Regulation of interleukin‐1 beta secretion from macrophages via modulation of potassium ion (K⁺) channel activity