Insights on the NF-κB System Using Live Cell Imaging: Recent Developments and Future Perspectives

Kizilirmak, Cise; Bianchi, Marco E.; Zambrano, Samuel

doi:10.3389/fimmu.2022.886127

Cited by 8 publications

(7 citation statements)

References 101 publications

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“…The immediate target of NF-κB is IκBα itself, which associates and sequesters NF-κB back into the cytoplasm terminating the transcriptional response. During sustained stimulation, these events repeat as NF-κB oscillations and eventually dampen out depending on the stimulus strength (DeFelice et al 2019; Kizilirmak, Bianchi, and Zambrano 2022). Intermediate stimulus promotes multiple rounds of steadfast NF-κB activities while strong stimulus promotes NF-κB activities with high initial amplitude but dampens out shortly (DeFelice et al 2019).…”

Section: Resultsmentioning

confidence: 99%

Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKε-dependent activation of NF-κB

Chan,

Sun,

Bhushan

et al. 2023

Preprint

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The corneal epithelium at the ocular surface is constantly exposed to the environment and represents the first line of defense against infection, mechanical injury or chemical irritation. Through TLR-mediated recognition of pathogen- and damage-associated molecular patterns, it engages in direct antimicrobial responses and alerts the immune system on intruder and tissue damage by secreting pro-inflammatory and chemotactic cytokines that promote immune cell infiltration. How the corneal epithelium downregulates TLR signaling is unclear, yet it highly expresses keratin 6a (K6a), a cytoskeletal protein that has emerged to play essential regulatory roles in corneal innate immune response. Here we report that mice harboring genetic deletion of K6a are more susceptible to developing bacterial keratitis with unresolved corneal opacification and higher bacterial load. Such disease phenotype is caused by the increased pro-inflammatory cytokine and chemokine secretions from the K6a-null corneal epithelium, which further promotes the infiltration of immune cells and their associated pro-inflammatory response. Using human corneal epithelial cells immortalized by telomerase reverse transcriptase (hTCEpi cells), we demonstrated that knocking down K6a enhances NF-κB/ RelA-dependent cytokine and chemokine expression. Moreover, proteomic screen reveals that K6a interacts with ELKS, a critical NEMO-binding scaffold that links between canonical IKKα/β and the principal cytoplasmic inhibitor of RelA, i.e. IκBα., to promote its phosphorylation and degradation. Surprisingly, K6a does not antagonize any of these canonical NF-κB signaling events. Instead, we found that ELKS in addition to canonical IKKs interacts with the atypical IKK member IKKϵ. Furthermore, knockdown of K6a in hTCEpi cells promotes ELKS-dependent phosphoactivation of IKKϵ, which in turn phosphorylates and activates RelA. Our study thus demonstrated an unexpected role of cytosolic K6a as a novel negative regulator of TLR/NF-κB signaling in preventing excess proinflammatory cytokine and chemokine expressions. It further highlighted the functional importance of ELKS as a common signaling scaffold for both canonical and atypical IKK-dependent activation of NF-κB in corneal epithelial cells. Using both IKK classes other than only canonical IKKs for TLR/NF-κB induction as in other cell types including myeloid immune cells suggest that the cornea epithelium is more flexible in modulating its inflammatory response, which could greatly minimize corneal damage while preserving its essential functions for barrier protection and light refraction.

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Section: Resultsmentioning

confidence: 99%

Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKε-dependent activation of NF-κB

Chan,

Sun,

Bhushan

et al. 2023

Preprint

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“…The crucial role as a mediator of the inflammatory responses, together with the finding that the activation or inhibition of NF-kB can induce or reverse, respectively, the main features of aged organisms, has brought NF-kB under consideration as a key TF that drives the biological aging process [ 88 ]. In this framework, the identification of genes modulated by NF-kB can be considered a cutting-edge issue [ 89 , 90 , 91 ].…”

Section: Discussionmentioning

confidence: 99%

A Data-Mining Approach to Identify NF-kB-Responsive microRNAs in Tissues Involved in Inflammatory Processes: Potential Relevance in Age-Related Diseases

Micolucci

Matacchione

Albertini

et al. 2023

IJMS

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The nuclear factor NF-kB is the master transcription factor in the inflammatory process by modulating the expression of pro-inflammatory genes. However, an additional level of complexity is the ability to promote the transcriptional activation of post-transcriptional modulators of gene expression as non-coding RNA (i.e., miRNAs). While NF-kB’s role in inflammation-associated gene expression has been extensively investigated, the interplay between NF-kB and genes coding for miRNAs still deserves investigation. To identify miRNAs with potential NF-kB binding sites in their transcription start site, we predicted miRNA promoters by an in silico analysis using the PROmiRNA software, which allowed us to score the genomic region’s propensity to be miRNA cis-regulatory elements. A list of 722 human miRNAs was generated, of which 399 were expressed in at least one tissue involved in the inflammatory processes. The selection of “high-confidence” hairpins in miRbase identified 68 mature miRNAs, most of them previously identified as inflammamiRs. The identification of targeted pathways/diseases highlighted their involvement in the most common age-related diseases. Overall, our results reinforce the hypothesis that persistent activation of NF-kB could unbalance the transcription of specific inflammamiRNAs. The identification of such miRNAs could be of diagnostic/prognostic/therapeutic relevance for the most common inflammatory-related and age-related diseases.

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“…NF-κB is an inducible transcription factor controlled by signal activation cascades ( Rinkenbaugh et al, 2021 ). NF-κB controls many genes involved in the inflammatory immune response, cell cycle progression, apoptosis inhibition, and cell adhesion, thus promoting a chronic inflammatory response ( Kizilirmak et al, 2022 ). In fact, in rheumatic diseases, NF-κB is activated by constituent type.…”

Section: Discussionmentioning

confidence: 99%

Detecting potential mechanism of vitamin D in treating rheumatoid arthritis based on network pharmacology and molecular docking

Luo

Chen

et al. 2022

Front. Pharmacol.

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Aim: Vitamin D plays a vital role in Rheumatoid arthritis (RA). However, the mechanism of vitamin D and rheumatism is still unclear. Therefore, a strategy based on network pharmacology and molecular docking was used to explore the mechanism of vitamin D and RA.Methods: The targets of RA were obtained from the GeneCards database and Therapeutic Targets Database, and the targets of vitamin D were obtained from the Drugbank database and STITCH database. Next, overlapping genes were identified by Venny, and further Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and molecular docking analyses were performed.Results: A total of 1,139 targets of RA and 201 targets of vitamin D were obtained. A total of 76 overlapping genes were identified by Venny. The enrichment analysis showed that cell proliferation, immune response, and apoptotic process were the critical biological processes of vitamin D in treating RA. Antifolate resistance, osteoclast differentiation, and the nuclear factor-kappa B (NF-κB) signalling pathway are fundamental mechanisms of vitamin D in treating RA. According to further molecular docking, ALB, TNF, CASP3, and TP53 may be important punctuation points or diagnostic markers for future RA treatment.Conclusion: By analysing overlapping genes of diseases and drugs, this study confirmed that ALB, TNF, CASP3, and TP53 may be essential markers or diagnostic markers for future RA treatment.

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Insights on the NF-κB System Using Live Cell Imaging: Recent Developments and Future Perspectives

Cited by 8 publications

References 101 publications

Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKε-dependent activation of NF-κB

Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKε-dependent activation of NF-κB

A Data-Mining Approach to Identify NF-kB-Responsive microRNAs in Tissues Involved in Inflammatory Processes: Potential Relevance in Age-Related Diseases

Detecting potential mechanism of vitamin D in treating rheumatoid arthritis based on network pharmacology and molecular docking

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