Cutting Edge: TRAF6 Mediates TLR/IL-1R Signaling–Induced Nontranscriptional Priming of the NLRP3 Inflammasome

Xing, Yue; Yao, Xiaomin; Li, Hua; Xue, Guang; Guo, Qiuhong; An, Liguo; Zhang, Yan; Meng, Guangxun

doi:10.4049/jimmunol.1700175

Cited by 131 publications

(97 citation statements)

References 23 publications

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“…Furthermore, we observed the inhibition of RIPK2, which is a potent activator of NF-κB and inducer of apoptosis. In addition, we observed the downregulation of TRAF6 gene expression, which may inhibit caspase-1 cleavage, pyroptosis, and pre-synthesized IL-18 secretion (Xing et al, 2017). Upregulation of IL-6 and TXNIP genes upon CRID3 exposure may help in reducing oxidative stress and inflammatory response.…”

Section: Cytokine Release Inhibitory Drug 3 Inhibits Inflammasome Regmentioning

confidence: 77%

Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model

Atluri

Tiwari

Rodriguez

et al. 2020

Front. Aging Neurosci.

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Alzheimer's disease (AD) is a growing global threat to healthcare in the aging population. In the USA alone, it is estimated that one in nine persons over the age of 65 years is living with AD. The pathology is marked by the accumulation of amyloid-beta (Aβ) deposition in the brain, which is further enhanced by the neuroinflammatory process. Nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) are the major neuroinflammatory pathways that intensify AD pathogenesis. Histone deacetylase 2 (HDAC2)-mediated epigenetic mechanisms play a major role in the genesis and neuropathology of AD. Therefore, therapeutic drugs, which can target Aβ production, NLRP3 activation, and HDAC2 levels, may play a major role in reducing Aβ levels and the prevention of associated neuropathology of AD. In this study, we demonstrate that withaferin A (WA), an extract from Withania somnifera plant, significantly inhibits the Aβ production and NF-κB associated neuroinflammatory molecules' gene expression. Furthermore, we demonstrate that cytokine release inhibitory drug 3 (CRID3), an inhibitor of NLRP3, significantly prevents inflammasomemediated gene expression in our in vitro AD model system. We have also observed that mithramycin A (MTM), an HDAC2 inhibitor, significantly upregulated the synaptic plasticity gene expression and downregulated HDAC2 in SH-SY5Y cells overexpressing amyloid precursor protein (SH-APP cells). Therefore, the introduction of these agents targeting Aβ production, NLRP3-mediated neuroinflammation, and HDAC2 levels will have a translational significance in the prevention of neuroinflammation and associated neurodegeneration in AD patients.

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Section: Cytokine Release Inhibitory Drug 3 Inhibits Inflammasome Regmentioning

confidence: 77%

Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model

Atluri

Tiwari

Rodriguez

et al. 2020

Front. Aging Neurosci.

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“…TRAF6 has been shown to mediate IL-1R signalling-induced non-transcriptional priming of the NLRP3 inflammasome. 37 Recently, it has been shown that circulating levels of cell death markers (cK18, K18) were significantly lower in patients with cirrhosis with previous AD. This may reflect a dominant cell death (IL-1α) response in individuals without prior AD, but an NLRP3 response (IL-1β) if there has been prior AD.…”

Section: Discussionmentioning

confidence: 99%

Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation

Monteiro¹,

Grandt

Uschner

et al. 2020

Gut

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ObjectiveSystemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients.Design249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured.ResultsPatients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1β detection rates in patients with ACLF were confirmed in the two external cohorts.ConclusionPrevious AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis.

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“…29 Importantly, inhibiting the inflammasome restores normal hematopoiesis 29 and protects against the development of cardiovascular disease in TET2-deficient mice. 30 TRAF6 is involved in TLR-mediated priming of the NLRP3 inflammasome in BM-derived macrophages, 31 suggesting that TLR signaling via TRAF6 is also linked to inflammasome activation in MDS.…”

Section: Functional Evidence Of Innate Immune Signaling Dysregulationmentioning

confidence: 99%

Chronic immune response dysregulation in MDS pathogenesis

Barreyro

Chlon

Starczynowski

2018

Blood

172

166

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Chronic innate immune signaling in hematopoietic cells is widely described in myelodysplastic syndromes (MDS), and innate immune pathway activation, predominantly via pattern recognition receptors, increases the risk of developing MDS. An inflammatory component to MDS has been reported for many years, but only recently has evidence supported a more direct role of chronic innate immune signaling and associated inflammatory pathways in the pathogenesis of MDS. Here we review recent findings and discuss relevant questions related to chronic immune response dysregulation in MDS.

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Cutting Edge: TRAF6 Mediates TLR/IL-1R Signaling–Induced Nontranscriptional Priming of the NLRP3 Inflammasome

Cited by 131 publications

References 23 publications

Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model

Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model

Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation

Chronic immune response dysregulation in MDS pathogenesis

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