The BET inhibitor attenuates the inflammatory response and cell migration in human microglial HMC3 cell line

Baek, Mina; Yoo, Eunyoung; Choi, Hae In; An, Ga Yeong; Chai, Jin Choul; Lee, Young Seek; Jung, Kyoung Hwa; Chai, Young Gyu

doi:10.1038/s41598-021-87828-1

Cited by 36 publications

(40 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The transcriptomic analysis of ESM-iBET (GSK3361191)-treated monocytes demonstrates a potent inhibitory effect on multiple inflammation related genes and pathways. This is in line with earlier reports using other iBET in human primary monocytes [ 50 ], human and murine microglial cell lines [ 51 , 52 ], and murine bone marrow derived macrophages [ 53 ] Additionally, we demonstrated a higher potency of ESM-iBET (GSK3361191) compared to iBET (GSK3235220) control at a low dose of 40 nM. Among the downregulated inflammatory genes, we could identify multiple targets of therapeutic relevance to CD, such as IL12B and TNFα, known therapeutic targets of biological agents such as ustekinumab, infliximab, or adalimumab (2).…”

Section: Discussionsupporting

confidence: 93%

A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease

Elfiky

Hageman

Becker

et al. 2022

Cells

View full text Add to dashboard Cite

Background: Myeloid cells are critical determinants of the sustained inflammation in Crohn’s Disease (CD). Targeting such cells may be an effective therapeutic approach for refractory CD patients. Bromodomain and extra-terminal domain protein inhibitors (iBET) are potent anti-inflammatory agents; however, they also possess wide-ranging toxicities. In the current study, we make use of a BET inhibitor containing an esterase sensitive motif (ESM-iBET), which is cleaved by carboxylesterase-1 (CES1), a highly expressed esterase in mononuclear myeloid cells. Methods: We profiled CES1 protein expression in the intestinal biopsies, peripheral blood, and CD fistula tract (fCD) cells of CD patients using mass cytometry. The anti-inflammatory effect of ESM-iBET or its control (iBET) were evaluated in healthy donor CD14+ monocytes and fCD cells, using cytometric beads assay or RNA-sequencing. Results: CES1 was specifically expressed in monocyte, macrophage, and dendritic cell populations in the intestinal tissue, peripheral blood, and fCD cells of CD patients. ESM-iBET inhibited IL1β, IL6, and TNFα secretion from healthy donor CD14+ monocytes and fCD immune cells, with 10- to 26-fold more potency over iBET in isolated CD14+ monocytes. Transcriptomic analysis revealed that ESM-iBET inhibited multiple inflammatory pathways, including TNF, JAK-STAT, NF-kB, NOD2, and AKT signaling, with superior potency over iBET. Conclusions: We demonstrate specific CES1 expression in mononuclear myeloid cell subsets in peripheral blood and inflamed tissues of CD patients. We report that low dose ESM-iBET accumulates in CES1-expressing cells and exerts robust anti-inflammatory effects, which could be beneficial in refractory CD patients.

show abstract

Section: Discussionsupporting

confidence: 93%

A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease

Elfiky

Hageman

Becker

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…In contrast, JQ1 treatment significantly suppressed CD83 expression proportionally with higher JQ1 concentration, while NFKBIA expression slightly increased ( Fig 5H , right), suggesting that CD83 gene expression was more highly controlled by BRD4, but NFKBIA was not. While we speculate that this difference is caused secondary to the initial accessibility in the enhancer region of NFKBIA in the absence of stimuli ( Fig 3A ) and that the chromatin accessibility change was comparably small upon stimulation ( Fig 3C ), there might be other unknown mechanisms causing the increase in gene expression, which have been previously reported [ 43 ].…”

Section: Resultsmentioning

confidence: 54%

Enhanced transcriptional heterogeneity mediated by NF-κB super-enhancers

et al. 2022

View full text Add to dashboard Cite

The transcription factor NF-κB, which plays an important role in cell fate determination, is involved in the activation of super-enhancers (SEs). However, the biological functions of the NF-κB SEs in gene control are not fully elucidated. We investigated the characteristics of NF-κB-mediated SE activity using fluorescence imaging of RelA, single-cell transcriptome and chromatin accessibility analyses in anti-IgM-stimulated B cells. The formation of cell stimulation-induced nuclear RelA foci was abolished in the presence of hexanediol, suggesting an underlying process of liquid-liquid phase separation. The gained SEs induced a switch-like expression and enhanced cell-to-cell variability in transcriptional response. These properties were correlated with the number of gained cis-regulatory interactions, while switch-like gene induction was associated with the number of NF-κB binding sites in SE. Our study suggests that NF-κB SEs have an important role in the transcriptional regulation of B cells possibly through liquid condensate formation consisting of macromolecular interactions.

show abstract

“…Differential expression analysis between MG from tumor center and periphery revealed a highly significant downregulation of inflammatory genes in the peripheral MG. This included scavenger receptors ( CD36 and MARCO ), chemokines ( CXCL3 and CCL20 ) and immune receptors ( IL7R [15] and CD109 , a negative regulator of TGF-β signaling [16]) as well as genes involved in cell growth ( CSRP1 ) and cell metabolism ( SMPDL3A [17] and SDS ) (Fig. 3a and Supplementary Table 3).…”

Section: Resultsmentioning

confidence: 99%

Single-cell characterization of human GBM reveals regional differences in tumor-infiltrating leukocyte activation

Schmassmann

Roux

Dettling

et al. 2022

Preprint

View full text Add to dashboard Cite

Glioblastoma (GBM) harbors a highly immunosuppressive tumor microenvironment (TME) which influences glioma growth. Major efforts have been undertaken to describe the TME on a single-cell level. However, human data on regional differences within the TME remain scarce. Here, we performed high-depth single-cell RNA sequencing (scRNAseq) on paired biopsies from the tumor center, peripheral infiltration zone and blood of five primary GBM patients. Through analysis of > 45'000 cells, we revealed a regionally distinct transcription profile of microglia (MG) and monocyte-derived macrophages (MdMs) and an impaired activation signature in the tumor-peripheral cytotoxic-cell compartment. Comparing tumor-infiltrating CD8+ T cells with circulating cells identified CX3CR1high and CX3CR1int CD8+ T cells with effector and memory phenotype, respectively, enriched in blood but absent in the TME. Tumor CD8+ T cells displayed a tissue-resident memory phenotype with dysfunctional features. Our analysis provides a large-scale dissection of GBM-associated leukocytes, serving as a reference map of human GBM-TME.

show abstract

The BET inhibitor attenuates the inflammatory response and cell migration in human microglial HMC3 cell line

Cited by 36 publications

References 59 publications

A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease

A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease

Enhanced transcriptional heterogeneity mediated by NF-κB super-enhancers

Single-cell characterization of human GBM reveals regional differences in tumor-infiltrating leukocyte activation

Contact Info

Product

Resources

About