Limiting inflammation—the negative regulation of NF-κB and the NLRP3 inflammasome

Afonina, Inna S.; Zhong, Zhenyu; Karin, Michael; Beyaert, Rudi

doi:10.1038/ni.3772

Cited by 632 publications

(442 citation statements)

References 114 publications

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“…In the context of NF-κB regulation, one of the best characterized RBPs is Tristetraprolin (TTP). TTP is considered a prototypic member of the RBPs and regulates NF-κB signaling by facilitating mRNA degradation [3, 118]. Specifically, TTP binds to mRNAs rich in AU-rich elements (AREs), which includes TNF and IL-23, and induces degradation [119].…”

Section: Post-transcriptional Inhibitionmentioning

confidence: 99%

“…This process is typically reversible, allowing a high level of temporal or tunable control, and usually occurs on serine, threonine, or tyrosine residues. In the NF-κB signaling pathway, phosphorylation can induce conformational changes in proteins such as IRAK and the IKK kinases, resulting in the release of auto-inhibition and increased enzymatic activity [3]. Conformation changes associated with phosphorylation can also promote or facilitate protein-protein interactions, such as those associated with IκBα or caspase-recruitment-domain (CARD) proteins [3].…”

Section: Post-translational Inhibitionmentioning

confidence: 99%

“…Indeed, there is a reinvigorated interest in better defining mechanisms associated with the negative regulation of NF-κB signaling, as evidenced by the increasing number of recent publications and reviews on this topic. For example, an excellent review by Afonina et al was recently published that focused on the negative regulation of NF-κB signaling and the NLRP3 inflammasome [3]. Here, we do not significantly cover NLRP3 inflammasome regulation or modulation.…”

Section: Introductionmentioning

confidence: 97%

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Modulating inflammation through the negative regulation of NF-κB signaling

Rothschild

McDaniel

Ringel‐Scaia

et al. 2018

Journal of Leukocyte Biology

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Immune system activation is essential to thwart the invasion of pathogens and respond appropriately to tissue damage. However, uncontrolled inflammation can result in extensive collateral damage underlying a diverse range of auto-inflammatory, hyper-inflammatory, and neoplastic diseases. The NF-κB signaling pathway lies at the heart of the immune system and functions as a master regulator of gene transcription. Thus, this signaling cascade is heavily targeted by mechanisms designed to attenuate overzealous inflammation and promote resolution. Mechanisms associated with the negative regulation of NF-κB signaling are currently under intense investigation and have yet to be fully elucidated. Here, we provide an overview of mechanisms that negatively regulate NF-κB signaling through either attenuation of signal transduction, inhibition of posttranscriptional signaling, or interference with posttranslational modifications of key pathway components. While the regulators discussed for each group are far from comprehensive, they exemplify common mechanistic approaches that inhibit this critical biochemical signaling cascade. Despite their diversity, a commonality among these regulators is their selection of specific targets at key inflection points in the pathway, such as TNF-receptor-associated factor family members or essential kinases. A better understanding of these negative regulatory mechanisms will be essential to gain greater insight related to the maintenance of immune system homeostasis and inflammation resolution. These processes are vital elements of disease pathology and have important implications for targeted therapeutic strategies.

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Section: Post-transcriptional Inhibitionmentioning

confidence: 99%

Section: Post-translational Inhibitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Modulating inflammation through the negative regulation of NF-κB signaling

Rothschild

McDaniel

Ringel‐Scaia

et al. 2018

Journal of Leukocyte Biology

View full text Add to dashboard Cite

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“…In order to control such potential harmful effect of inflammation, inflammatory pathways and their activators are tightly controlled by a network of regulators and feedback loops (3).…”

mentioning

confidence: 99%

The NLR family pyrin domain–containing 11 protein contributes to the regulation of inflammatory signaling

Ellwanger

Becker

Kienes

et al. 2018

Journal of Biological Chemistry

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Mammalian NLR proteins contribute to the regulation and induction of innate and adaptive immunity in mammals although the function of about half of the currently identified NLR proteins remains poorly characterized. Here we analysed the function of the primate-specific NLRP11 gene product. We show that NLRP11 is highly expressed in immune cells, including myeloid cells, B cells and some B cell lymphoma lines. Overexpression of NLRP11 in human cells did not trigger key innate immune signalling pathways including NF-κB and type I interferon responses. NLRP11 harbours a pyrin domain (PYD), which is responsible for inflammasome formation in related NLR proteins. However, NLRP11 did neither interact with the inflammasome adaptor protein ASC nor did it trigger caspase-1 activation. By contrast, expression of NLRP11 specifically repressed NF-κB and type I interferon responses, two key innate immune pathways involved in inflammation. This effect was independent of the PYD domain and ATPase activity of NLRP11. SiRNA-mediated knock-down of NLRP11 in human myeloid THP1 cells validated these findings and revealed enhanced lipopolysaccharide (LPS) and Sendai Virus (SeV)-induced cytokine and interferon responses, respectively in cells with reduced NLRP11 expression. In summary, our work identifies a novel role of NLRP11 in the regulation of inflammatory responses in human cells.An inflammatory response is triggered in response to cell damage and to defend against invading pathogens. In mammals, this is mediated by the activation of cellular pathways cumulating into the release of cytokines, chemokines and interferons. Downstream, this orchestrates recruitment of effector cells, alerts a systemic response and restores tissue homeostasis (1). Activation of pattern-recognition receptors (PRRs 2 ), expressed in and on host cells, which respond towards pathogen-derived substances, cell damage and stress, initiate this response. On the cellular level, inflammation is mediated by the activation of proinflammatory signaling cascades such as the activation of caspase-1, NF-κB, IRFs, amongst others. Chronic In humans, the TLR, NLR and C-type lectin family members are the most relevant PRRs. Many mammalian NLR proteins have been associated with multiple functions in inflammation and innate and adaptive immune responses (4) and dysfunctions in NLRs are associated with a range of diseases including Crohn's disease, periodic fever syndromes and Blau Syndrom (5), highlighting their physiologic relevance NLR proteins have a typical tripartite domain architecture and can be classified functionally according to their N-terminal domain which is, in most cases a CARD or PYD domain (6). Most but not all PYD-containing NLRs can interact with the adaptor molecule ASC to form high molecular weight complexes in cells, referred to as inflammasomes, which function as a platform for the activation of caspase-1 and subsequent IL-1β and IL-18 processing. The NLR family-member pyrin domain-containing protein 11 (NLRP11, NALP11, NOD17, PYPAF6, PAN...

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“…Cytokines in turn not only promote MM cell growth, but also increase resistance to conventional therapies [12, 13]. In recent years, more and more studies have shown that an inflammasome in tumor microenvironments can trigger carcinogenesis, and has significant impacts on tumor immunity and immunotherapy, thus providing new insight into the effective therapies [14, 15]. The most studied inflammasome is the NLRP3 inflammasome, and mounting evidences support that the NLRP3 inflammasome plays an important role in the development of malignant tumors [16, 17].…”

Section: Discussionmentioning

confidence: 99%

The Genetic Polymorphisms of NLRP3 Inflammasome Associated with T Helper Cells in Patients with Multiple Myeloma

Zhao

Hua

Yan

et al. 2018

Journal of Immunology Research

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The pathogenesis of multiple myeloma (MM) remains unclear and the NLRP3 inflammasome has been more and more recognized in the progression of many diseases. To investigate the role of the NLRP3 inflammasome in MM, we determined the genetic polymorphisms and expression of NLRP3 inflammasome-related genes (IL-1β, IL-18, CARD8, and NF-κB) in MM patients, and explored their clinical relevance. Furthermore, we investigated the relationship of the NLRP3 inflammasome with Th cells in MM. Our study showed that the CARD8-C10X (rs2043211) AT genotype contributed to the susceptibility of MM. CARD8-C10X TT patients had earlier clinical stage. The WBC count in the three CARD8 genotypes showed an increasing trend (AA

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Limiting inflammation—the negative regulation of NF-κB and the NLRP3 inflammasome

Cited by 632 publications

References 114 publications

Modulating inflammation through the negative regulation of NF-κB signaling

Modulating inflammation through the negative regulation of NF-κB signaling

The NLR family pyrin domain–containing 11 protein contributes to the regulation of inflammatory signaling

The Genetic Polymorphisms of NLRP3 Inflammasome Associated with T Helper Cells in Patients with Multiple Myeloma

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