Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5

Buxadé, María; Lunazzi, Giulia; Minguillón, Jordi; Iborra, Salvador; Berga-Bolaños, Rosa; Val, Margarita Del; Aramburu, J.; López-Rodrı́guez, Cristina

doi:10.1084/jem.20111569

Cited by 141 publications

(220 citation statements)

References 78 publications

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“…We report prominent expression of AR, TauT, and SMIT in the perifascicular atrophic fibers of DM, accompanied by increased/induced expression of other known NFAT5 molecular targets HSP70, 27 iNOS, 28 and CCL2. 29 As was the case earlier for iNOS, 30 we could, however, not confirm a significant increase of AR protein levels in DM muscle extracts via western blotting, presumably because of its expression being limited to the affected perifascicular areas.…”

Section: Osmolyte Pathway Activation In Dmmentioning

confidence: 74%

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

Paepe

Martin

Herbelet

et al. 2016

Laboratory Investigation

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Alongside well-known nuclear factor κB (NFκB) and its associated cytokine networks, nuclear factor of activated T cells 5 (NFAT5), the master regulator of cellular osmoprotective programs, comes forward as an inflammatory regulator. To gain insight into its yet unexplored role in muscle disease, we studied the expression of NFAT5 target proteins involved in osmolyte accumulation: aldose reductase (AR), taurine transporter (TauT), and sodium myo-inositol co-transporter (SMIT). We analyzed idiopathic inflammatory myopathy and Duchenne muscular dystrophy muscle biopsies and myotubes in culture, using immunohistochemistry, immunofluorescence, and western blotting. We report that the level of constitutive AR was upregulated in patients, most strongly so in Duchenne muscular dystrophy. TauT and SMIT expression levels were induced in patients' muscle fibers, mostly representing regenerating and atrophic fibers. In dermatomyositis, strong staining for AR, TauT, and SMIT in atrophic perifascicular fibers was accompanied by staining for other molecular NFAT5 targets, including chaperones, chemokines, and inducible nitric oxide synthase. In these fibers, NFAT5 and NFκB p65 staining coincided, linking both transcription factors with this important pathogenic hallmark. In sporadic inclusion body myositis, SMIT localized to inclusions inside muscle fibers. In addition, SMIT was expressed by a substantial subset of muscle-infiltrating macrophages and T cells in patient biopsies. Our results indicate that osmolyte pathways may contribute to normal muscle functioning, and that activation of AR, TauT, and SMIT in muscle inflammation possibly contributes to the tissue's failing program of damage control.

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Section: Osmolyte Pathway Activation In Dmmentioning

confidence: 74%

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

Paepe

Martin

Herbelet

et al. 2016

Laboratory Investigation

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“…However, we found that RON activity was associated with an overall immunosuppressive state. For example, macrophage genes known to be upregulated by the inflammatory stimulus lipopolysaccharide (LPS) 44 were downregulated in the presence of MSP stimulation ( Fig S3a,b ). Differentially expressed genes in our study were mostly in agreement with findings reported by Chaudhuri et al, who used microarray technology to investigate gene expression changes in macrophages 20 hours after MSP treatment 31 ( Fig S4 ).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

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“…In the broader context, NFAT5-mediated adaptation to hyperosmotic stress is crucial to the development and function of macrophages (45) and lymphocytes (62). The current paradigm of cellular osmotic regulation is focused on the activation of target genes, post-translational modification or other direct interactions of NFAT5, which mediates this program (63)(64)(65)(66)(67).…”

Section: Discussionmentioning

confidence: 99%

“…PU.1 is a critical transcriptional regulator in myelopoiesis (43), and PU.1 target genes harbor binding sites that correspond to high affinity sequences (44). We analyzed differential gene expression in bone marrow-derived macrophages from NFAT5 knock-out mice relative to their isogenic wild type and identified a core set of 24 genes (NCBI GEO accession number GSE26343; adjusted p Ͻ 0.05) (45). We then screened these NFAT5-dependent genes against data sets in which PU.1 or another (control) pro-tein is induced, knocked down, or knocked out in similar cellular backgrounds under resting (unstimulated) conditions (Fig.…”

Section: Pu1 Target Genes Are Enriched Among Genes Thatmentioning

confidence: 99%

Mechanistic Heterogeneity in Site Recognition by the Structurally Homologous DNA-binding Domains of the ETS Family Transcription Factors Ets-1 and PU.1

Wang

Linde

Munde

et al. 2014

Journal of Biological Chemistry

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Background: ETS family transcription factors recognize DNA via structurally conserved DNA-binding domains that share limited amino acid homology. Results: DNA recognition by the ETS domains of Ets-1 and PU.1, two extreme sequence-divergent paralogs, was compared. Conclusion: Preferential hydration differentiates DNA recognition by Ets-1 and PU.1. Significance: Preferential hydration represents a potential mechanism for PU.1 regulation and its activity as a pioneer transcription factor in vivo.

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Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5

Abstract: NFAT5 regulates the induction of TLR-stimulated genes with constitutive binding to the Tnf promoter regardless of TLR ligation and recruitment to Nos2 and Il6 dependent on TLR activation and IKKb.

Cited by 141 publications

References 78 publications

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Mechanistic Heterogeneity in Site Recognition by the Structurally Homologous DNA-binding Domains of the ETS Family Transcription Factors Ets-1 and PU.1

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