The MNK-1/eIF4E pathway as a new therapeutic pathway to target inflammation and remodelling in asthma

Seidel, Petra; Sun, Qingzhu; Costa, Luigi; Lardinois, Didier; Tamm, Michael; Roth, Michael

doi:10.1016/j.cellsig.2016.07.004

Cited by 20 publications

(25 citation statements)

References 34 publications

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“…*p < 0.05; **p < 0.01; ***p < 0.001. transcripts relies on the MNK1/2-eIF4E axis [11,22,23,33,34,43]. In regards to CCL5 and CXCL10, several lines of evidence indicate that MNK1/2 regulate their expression through different mechanisms [14,33,34,44]. Activation of MNK1/2 was shown to be required for late transcription of Ccl5 mRNA via translational control of the transcription factor RFLAT-1 in IL-2-treated T cells [34].…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, inhibition of MNK1/2 abrogated Cxcl10 transcription and CXCL10 secretion in TNF stimulated smooth muscle cells [14]. Interestingly, the authors also showed that CCL5 and CXCL10 protein expression was reduced in MNK1 knock-down cells compared to WT controls [14], yet no experimental evidence on differential transcription and/or mRNA translation was provided. Of note, polysome-profiling of WT and eIF4E S209A KI MEFs quantified by microarray did not identify Ccl5 and Cxcl10 as targets of translational control via the MNK1/2-eIF4E axis [33].…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with the pivotal role of mTORC1 and MNK1/2 in translational control of immune responses (reviewed in ref. [11]), emerging evidence points to their involvement in the regulation of CCL5 and CXCL10 protein synthesis [12][13][14][15][16][17]. Indeed, the use of rapamycin, an allosteric inhibitor of mTOR, blocks CCL5 secretion under proinflammatory conditions in vitro and in vivo [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Translational repression of Ccl5 and Cxcl10 by 4E‐BP1 and 4E‐BP2 restrains the ability of mouse macrophages to induce migration of activated T cells

et al. 2019

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Signaling through the mechanistic target of rapamycin complex 1 (mTORC1) is a major regulatory node of pro‐inflammatory mediator production by macrophages (MΦs). However, it is still unclear whether such regulation relies on selective translational control by two of the main mTORC1 effectors, the eIF4E‐binding proteins 1 and 2 (4E‐BP1/2). By comparing translational efficiencies of immune‐related transcripts of MΦs from WT and 4E‐BP1/2 double‐KO (DKO) mice, we found that translation of mRNAs encoding the pro‐inflammatory chemokines CCL5 and CXCL10 is controlled by 4E‐BP1/2. Macrophages deficient in 4E‐BP1/2 produced higher levels of CCL5 and CXCL10 upon LPS stimulation, which enhanced chemoattraction of activated T cells. Consistent with this, treatment of WT cells with mTORC1 inhibitors promoted the activation of 4E‐BP1/2 and reduced CCL5 and CXCL10 secretion. In contrast, the phosphorylation status of eIF4E did not affect the synthesis of these chemokines since MΦs derived from mice harboring a non‐phosphorylatable form of the protein produced similar levels of CCL5 and CXCL10 to WT counterparts. These data provide evidence that the mTORC1‐4E‐BP1/2 axis contributes to regulate the production of chemoattractants by MΦs by limiting translation efficiency of Ccl5 and Cxcl10 mRNAs, and suggest that 4E‐BP1/2 act as immunological safeguards by fine‐tuning inflammatory responses in MΦs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Translational repression of Ccl5 and Cxcl10 by 4E‐BP1 and 4E‐BP2 restrains the ability of mouse macrophages to induce migration of activated T cells

et al. 2019

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“…However, for some diseases such as asthma and diabetic retinopathy, abnormal post-transcriptional regulation is key [40][41]. For such diseases, the inhibition of the post-transcriptional phase is considered more appropriate in the therapeutic strategy [40][41]. In the present study, CUDC-907 was found to inhibit the production of MCP-1 and IP-10 post-transcriptionally.…”

Section: Discussionmentioning

confidence: 52%

“…A large number of compounds are reported to inhibit the release of extracellular cytokines or chemokines, many of which suppress the expression levels by targeting the inflammatory signaling cascade [38][39]. However, for some diseases such as asthma and diabetic retinopathy, abnormal post-transcriptional regulation is key [40][41]. For such diseases, the inhibition of the post-transcriptional phase is considered more appropriate in the therapeutic strategy [40][41].…”

Section: Discussionmentioning

confidence: 99%

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Kase

Terashima

Ohta

et al. 2020

Preprint

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Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)-derived NNS disease model that reproduces several inflammatory phenotypes including the overproduction of monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein-10 (IP-10). Here we performed high-throughput compound screening (HTS) using this PSC-derived NNS model to find potential therapeutic candidates and identified CUDC-907 as an effective inhibitor of the release of MCP-1 and IP-10.CUDC-907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post-transcriptional. These findings suggest that HTS with PSC-derived disease models is useful for finding drug candidates for autoinflammatory diseases. Significance statementIn this study, we identified a histone deacetylase inhibitor CUDC-907 as a potential effective compound for ameliorating overproduction of inflammatory chemokines in an autoinflammatory disease named Nakajo-Nishimura syndrome. We performed high-throughput screening using pluripotent stem cell-derived monocytic cell lines. Our data prove the validity of screening system as a versatile platform for seeking candidate compounds for the treatment of congenital immunological disorders associated with monocytic lineage cells.

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Pluripotent stem cell-based screening identifies CUDC-907 as an effective compound for restoring the in vitro phenotype of Nakajo-Nishimura syndrome

Kase

Terashima

Ohta

et al. 2020

Stem Cells Translational Medicine

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Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)-derived NNS disease model that reproduces several inflammatory phenotypes including the overproduction of monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein-10 (IP-10). Here we performed high-throughput compound screening (HTS) using this PSC-derived NNS model to find potential therapeutic candidates and identified CUDC-907 as an effective inhibitor of the release of MCP-1 and IP-10. Short-term treatment of CUDC-907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post-transcriptional. These findings suggest that HTS with PSC-derived disease models is useful for finding drug candidates for autoinflammatory diseases. K E Y W O R D S chemokines, hereditary autoinflammatory diseases, high-throughput screening assays, histone deacetylase inhibitors, LMP7 protein, pluripotent stem cells 1 | INTRODUCTION Proteasome-associated autoinflammatory syndromes (PRAAS) are a recently defined group of autoinflammatory disorders caused by the mutations of proteasome subunits or their assembly factors. 1 PRAAS include diseases such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), 2 POMP-related auto-inflammation and immune dysregulation disease (PRAID), 3 and

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The MNK-1/eIF4E pathway as a new therapeutic pathway to target inflammation and remodelling in asthma

Cited by 20 publications

References 34 publications

Translational repression of Ccl5 and Cxcl10 by 4E‐BP1 and 4E‐BP2 restrains the ability of mouse macrophages to induce migration of activated T cells

Translational repression of Ccl5 and Cxcl10 by 4E‐BP1 and 4E‐BP2 restrains the ability of mouse macrophages to induce migration of activated T cells

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Pluripotent stem cell-based screening identifies CUDC-907 as an effective compound for restoring the in vitro phenotype of Nakajo-Nishimura syndrome

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