TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies

McGeough, Matthew D.; Wree, Alexander; Inzaugarat, María Eugenia; Haimovich, Ariela; Johnson, Casey D.; Peña, Carla A.; Goldbach‐Mansky, Raphaela; Broderick, Lori; Feldstein, Ariel E.; Hoffman, Hal M.

doi:10.1172/jci90699

Cited by 130 publications

(102 citation statements)

References 25 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Additionally, loss of TNF helped to protect against disease induced by NLRP3 mutations. 47 While NF-κB-dependent transcriptional regulation of Nlrp3 is the most well studied, other putative transcription factorbinding sites have been identified in the promoter region including Sp1, c-Myb, AP-1, and c-Ets, and disruption of the Sp1 site leads to a reduction in NLRP3 expression. 48 An additional study in human endothelial cells also found that NLRP3 was regulated by the sterol regulatory element-binding transcription factor 2 (SREBP2) binding between −1379 and −1368 bp.…”

Section: Upstream Regulatory Moleculesmentioning

confidence: 99%

Toward targeting inflammasomes: insights into their regulation and activation

2020

View full text Add to dashboard Cite

Inflammasomes are multi-component signaling complexes critical to the initiation of pyroptotic cell death in response to invading pathogens and cellular damage. A number of innate immune receptors have been reported to serve as inflammasome sensors. Activation of these sensors leads to the proteolytic activation of caspase-1, a proinflammatory caspase responsible for the cleavage of proinflammatory cytokines interleukin-1β and interleukin-18 and the effector of pyroptotic cell death, gasdermin D. Though crucial to the innate immune response to infection, dysregulation of inflammasome activation can lead to the development of inflammatory diseases, neurodegeneration, and cancer. Therefore, clinical interest in the modulation of inflammasome activation is swiftly growing. As such, it is imperative to develop a mechanistic understanding of the regulation of these complexes. In this review, we divide the regulation of inflammasome activation into three parts. We discuss the transcriptional regulation of inflammasome components and related proteins, the post-translational mechanisms of inflammasome activation, and advances in the understanding of the structural basis of inflammasome activation.

show abstract

Section: Upstream Regulatory Moleculesmentioning

confidence: 99%

Toward targeting inflammasomes: insights into their regulation and activation

2020

View full text Add to dashboard Cite

show abstract

“…Inhibiting the RAGE1 receptor with BoxA similarly inhibited HMGB1 transcriptional priming of NLRP3 and IL-1β maturation in mice microglia when exposed to chronic stress (Weber et al, 2015). More recent approaches involve using antagonists of the glucocorticoid receptor (Busillo et al, 2011) or of the TNFαR (McGeough et al, 2017) to prevent NLRP3 transcriptional priming. However, given the polymorphic forms of NLRP3 transcriptional priming it would be difficult to prevent NLRP3 transcription by inhibiting one pathway or even two of these pathways.…”

Section: Inhibition Of the Nlrp3 Inflammasome And Neuroinflammationmentioning

confidence: 99%

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Herman

Pasinetti

2018

Brain, Behavior, and Immunity

View full text Add to dashboard Cite

The production of inflammatory proteins by the innate immune system is a tightly orchestrated procedure that allows the body to efficiently respond to exogenous and endogenous threats. Recently, accumulating evidence has indicated that disturbances in the inflammatory response system not only provoke autoimmune disorders, but also can have deleterious effects on neuronal function and mental health. As inflammation in the brain is primarily mediated by microglia, there has been an expanding focus on the mechanisms through which these cells initiate and propagate neuroinflammation. Microglia can enter persistently active states upon their initial recognition of an environmental stressor and are thereafter prone to elicit amplified and persistent inflammatory responses following subsequent exposures to stressors. A recent focus on why primed microglia cells are susceptible to environmental insults has been the NLRP3 inflammasome. Its function within the innate immune system is regulated in such a manner that supports a role for the complex in gating neuroinflammatory responses. The activation of NLRP3 inflammasome in microglia results in the cleavage of zymogen inflammatory interleukins into functional forms that elicit a number of consequential effects in the local neuronal environment. There is evidence to support the principle that within primed neuroimmune systems a lowered threshold for NLRP3 activation can cause persistent neuroinflammation or the amplified production of inflammatory cytokines, such as IL-1β and IL-18. Over the course of an individual's lifetime, persistent neuroinflammation can subsequently lead to the pathophysiological signatures that define psychological disorders. Therefore, targeting the NLRP3 inflammasome complex may represent an innovative and consequential approach to limit neuroinflammatory states in psychiatric disorders, such as major depressive disorder.

show abstract

“…It is evidenced that mitochondrial ROS and release of oxidized mitochondrial DNA into cytosol can trigger activation of NLRP3 inflammasome (28)(29)(30)(31). Furthermore, it has been suggested that BCL2 and TNF that play roles in apoptosis and inflammation respectively, can regulate the NLRP3 inflammasome activation (28,(32)(33)(34). Given these data, our results, plus the well-known effects of stress on the neuroendocrine system, it seems that maternal separation stress experienced by parents can affect the components of NLRP3 inflammasome and molecules involved in inflammation with change in ROS, BCL2 and TNFα levels and subsequently result in increased production of IL-1β and IL-18.…”

Section: Discussionmentioning

confidence: 99%

Maternal separation stress experienced by parents affects ovarian function in first generation of mice

Khodamoradi

Khosravizadeh

Amini-Khoei

et al. 2020

Preprint

View full text Add to dashboard Cite

The maternal separation stress during postnatal development can adversely affect one's adulthood. Some parents' experiences may not only affect the phenotype of parents but also alter the reaction to environmental impacts in the offspring. The aim of this study is to investigate consequences of maternal separation stress in female first generation of mice whose parents were exposed to maternal separation stress. Maternal separation in pups was performed during post-natal days (PND) 2 to 14. Then, female pups of the first-generation were used in present study. The histological changes in ovaries, ROS production (using DCFH-DA assay), mRNA expression of NLRP3, ASC, caspase-1, TLR4, BAX, BCL2 and TNFα genes (using RT-PCR), levels of IL-18, IL-1β, ATP and GPx (using ELISA) and also protein expression of caspase-3 and NLRP3 (using immunocytochemistry) were assessed. Our findings showed that maternal separation stress experienced by parents significantly affects the numbers of primordial and primary follicles. Furthermore, ROS production increased and concentrations of ATP and GPx reduced in the first generation. Also, expression of cytokines and genes involved in inflammation and apoptosis including NLRP3, caspase-1, TLR4, TNFα, IL-1β, IL-18 and BCL2 were significantly affected in the first generation. Our results also showed that this stress significantly increased percentage of caspase-3 and NLRP3 positive cells in the ovarian tissue of the first generation. Our findings suggest that maternal separation stress experienced by parents may influence activation of inflammatory response in the ovarian tissue of their first generation which may induce apoptosis and consequently disturb folliculogenesis process.

show abstract

TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies

Cited by 130 publications

References 25 publications

Toward targeting inflammasomes: insights into their regulation and activation

Toward targeting inflammasomes: insights into their regulation and activation

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Maternal separation stress experienced by parents affects ovarian function in first generation of mice

Contact Info

Product

Resources

About