IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate macrophage activation

Kang, Ki‐Woon; Bachu, Mahesh; Park, Sung Ho; Kang, Keunsoo; Bae, Seyeon; Park‐Min, Kyung‐Hyun; Ivashkiv, Lionel B.

doi:10.1038/s41467-019-11147-3

Cited by 99 publications

(75 citation statements)

References 57 publications

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“…Many studies have revealed that STAT1 signaling is primarily activated by IFN‐γ in macrophages 33, 34 . Interestingly, some groups have reported that IFN‐γ even negatively regulated components of the LPS response 33, 35 . These support our results that disruption of Grx1 promoted the activity of STAT1 in IFN‐γ stimulated macrophages and consequently upregulated the transcription of downstream target genes such as CXCL9.…”

Section: Discussionsupporting

confidence: 90%

“…33,34 Interestingly, some groups have reported that IFN-γ even negatively regulated components of the LPS response. 33,35 These support our results that disruption of Grx1 promoted the activity of STAT1 in IFN-γ stimulated macrophages and consequently upregulated the transcription of downstream target genes such as CXCL9. However, the expressions of other M1-related molecules during the process of IFN-γ stimulation need to be investigated in the future.…”

Section: Discussionsupporting

confidence: 85%

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Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1

et al. 2020

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Background: Macrophage polarization affects tumor growth, metabolism, and many other tumor processes. M1 macrophages can promote antitumor immunity response. Signal transducer and activator of transcription 1 (STAT1) is one of the critical transcription factors in this process, which promotes the expression of a series of inflammatory molecules. STAT1 has been reported as a potential target of reactive oxygen species (ROS)-induced glutathionylation, while the glutathionylation of STAT1 in macrophages and its underlying regulatory mechanism remains unclear. Glutaredoxin 1 (Grx1) functions as a deglutathionylation enzyme, which regulates the activities of many proteins through reversing glutathionylation. Methods: GeneChip and RT-qPCR was first applied to test the mRNA level of Grx1 in M1 macrophages. Western blot was then used to evaluate the variations of the Grx1 protein expression in M1 macrophages. Next, immunoprecipitation was used to investigate the glutathionylated STAT1 in both wild-type and Grx1 −/− mouse macrophages. Finally, the induced alterations of STAT1 activity and function by Grx1 in M1 macrophage were examined by western blot and RT-qPCR. Results: In M1-type macrophages, the levels of Grx1 were elevated. Glutathionylation of STAT1 was negatively regulated by Grx1. Furthermore, depletion of Grx1 increased the activity of STAT1, and thereby promoted the mRNA level of C-X-C motif chemokine ligand 9 (CXCL9) during M1-type polarization of macrophages. Conclusions: Grx1 controlled deglutathionylation of STAT1, which in turn might regulate M1-type polarization of macrophages.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 85%

Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1

et al. 2020

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“…As an alternative approach, we utilized human OCPs adenovirally-transduced to express FLAG-tagged MEF2C, where high affinity and specificity FLAG antibodies enable detection of strong and specific signals in ChIP-qPCR assays. We identified three potential MEF2C binding sites, termed R1–R3, in the upstream region of the c-FOS promoter based on the publicly available ENCODE MEF2C ChIP-seq database obtained using the GM12878 cell line, an established lymphoblastoid cell line 30 and we also confirmed that the potential MEF2C binding sites were regions of open chromatin (detected by ATAC-seq) and were bound by PU.1, a lineage-determining transcription factor in human OCPs 31 (Fig. 6a , Supplementary Fig.…”

Section: Resultsmentioning

confidence: 56%

MEF2C regulates osteoclastogenesis and pathologic bone resorption via c-FOS

et al. 2021

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Osteoporosis is a metabolic bone disease with dysregulated coupling between bone resorption and bone formation, which results in decreased bone mineral density. The MEF2C locus, which encodes the transcription factor MADS box transcription enhancer factor 2, polypeptide C (MEF2C), is strongly associated with adult osteoporosis and osteoporotic fractures. Although the role of MEF2C in bone and cartilage formation by osteoblasts, osteocytes, and chondrocytes has been studied, the role of MEF2C in osteoclasts, which mediate bone resorption, remains unclear. In this study, we identified MEF2C as a positive regulator of human and mouse osteoclast differentiation. While decreased MEF2C expression resulted in diminished osteoclastogenesis, ectopic expression of MEF2C enhanced osteoclast generation. Using transcriptomic and bioinformatic approaches, we found that MEF2C promotes the RANKL-mediated induction of the transcription factors c-FOS and NFATc1, which play a key role in osteoclastogenesis. Mechanistically, MEF2C binds to FOS regulatory regions to induce c-FOS expression, leading to the activation of NFATC1 and downstream osteoclastogenesis. Inducible deletion of Mef2c in mice resulted in increased bone mass under physiological conditions and protected mice from bone erosion by diminishing osteoclast formation in K/BxN serum induced arthritis, a murine model of inflammatory arthritis. Our findings reveal direct regulation of osteoclasts by MEF2C, thus adding osteoclasts as a cell type in which altered MEF2C expression or function can contribute to pathological bone remodeling.

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“…Several TFs have been demonstrated to be involved in modulating the M2 phenotype of macrophages, such as PRDM1, MAF, STAT6, STAT3, HIF-1α, and C/EBPβ (10,(29)(30)(31)(32)(33). We assumed that AZD5153 epigenetically regulated the macrophage phenotype via alternating the expression levels of pivotal TFs.…”

Section: Azd5153 Depolarized M2-like Macrophages By Inhibiting Mafmentioning

confidence: 99%

BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages

Yang

et al. 2020

Front. Immunol.

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High-grade serous ovarian cancer (HGSOC), with its high recurrence rates, urges for reasonable therapeutic strategies that can prolong overall survival. A tumor microenvironment (TME) discloses prognostic and prospective information on cancer, such as the expression level of PD-1 or PD-L1. However, in HGSOC, the impact of the therapies aiming at these targets remains unsatisfying. Tumor-associated macrophages (TAMs) in HGSOC make up a large part of the TMEs and transform between diverse phenotypes under different treatments. AZD5153 inhibiting BRD4, as a potential therapeutic strategy for HGSOC, was demonstrated to confer controversial plasticity on TAMs, which shows the need to uncover its impact on TAMs in HGSOC. Therefore, we established models for TAMs and TAMs co-culturing with T lymphocytes in vitro. Via RT-PCR and flow cytometry, we find that AZD5153 resets TAMs from M2-type macrophages to M1-like macrophages, consequently promoting pro-inflammatory cytokine secretion and thus activating CD8 + cytotoxic T lymphocytes (CTLs) in vitro. This modification occurs on MAF transcripts in TAMs and modified by BRD4, which is the target of AZD5153. Importantly, the 3-D microfluid model demonstrates that AZD5153 sensitizes ovarian cancer to anti-PD-L1 therapy. Our results clarify that besides eliminating tumor cells directly, AZD5153 works as a regulator of the TAM phenotype, providing a novel strategy combining AZD5153 and PD-1/PD-L1 antibody that could benefit HGSOC patients.

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IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate macrophage activation

Cited by 99 publications

References 57 publications

Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1

Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1

MEF2C regulates osteoclastogenesis and pathologic bone resorption via c-FOS

BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages

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