Screening of compounds to identify novel epigenetic regulatory factors that affect innate immune memory in macrophages

Benjaskulluecha, Salisa; Boonmee, Atsadang; Pattarakankul, Thitiporn; Wongprom, Benjawan; Klomsing, Jeerameth; Palaga, Tanapat

doi:10.1038/s41598-022-05929-x

Cited by 15 publications

(31 citation statements)

References 51 publications

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“…Moreover, Ezh2 was one of the upregulated genes in macrophages with LPS tolerance found in our previous publication [ 43 ]. The screening of epigenetic inhibitors also demonstrated that the Ezh2 inhibitor enhances TNF-α expression in the LPS-tolerant macrophages [ 44 ]. Thus, the control of macrophage responses through the manipulations of epigenetics is interesting for controlling sepsis immune responses [ 13 , 45 ].…”

Section: Introductionmentioning

confidence: 99%

The Regulatory Roles of Ezh2 in Response to Lipopolysaccharide (LPS) in Macrophages and Mice with Conditional Ezh2 Deletion with LysM-Cre System

Kunanopparat

Leelahavanichkul

Visitchanakun

et al. 2023

IJMS

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The responses of macrophages to lipopolysaccharide (LPS) might determine the direction of clinical manifestations of sepsis, which is the immune response against severe infection. Meanwhile, the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, might interfere with LPS response. Transcriptomic analysis on LPS-activated wild-type macrophages demonstrated an alteration of several epigenetic enzymes. Although the Ezh2-silencing macrophages (RAW264.7), using small interfering RNA (siRNA), indicated a non-different response to the control cells after a single LPS stimulation, the Ezh2-reducing cells demonstrated a less severe LPS tolerance, after two LPS stimulations, as determined by the higher supernatant TNF-α. With a single LPS stimulation, Ezh2 null (Ezh2flox/flox; LysM-Crecre/−) macrophages demonstrated lower supernatant TNF-α than Ezh2 control (Ezh2fl/fl; LysM-Cre−/−), perhaps due to an upregulation of Socs3, which is a suppressor of cytokine signaling 3, due to the loss of the Ezh2 gene. In LPS tolerance, Ezh2 null macrophages indicated higher supernatant TNF-α and IL-6 than the control, supporting an impact of the loss of the Ezh2 inhibitory gene. In parallel, Ezh2 null mice demonstrated lower serum TNF-α and IL-6 than the control mice after an LPS injection, indicating a less severe LPS-induced hyper-inflammation in Ezh2 null mice. On the other hand, there were similar serum cytokines after LPS tolerance and the non-reduction of serum cytokines after the second dose of LPS, indicating less severe LPS tolerance in Ezh2 null mice compared with control mice. In conclusion, an absence of Ezh2 in macrophages resulted in less severe LPS-induced inflammation, as indicated by low serum cytokines, with less severe LPS tolerance, as demonstrated by higher cytokine production, partly through the upregulated Socs3.

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Section: Introductionmentioning

confidence: 99%

The Regulatory Roles of Ezh2 in Response to Lipopolysaccharide (LPS) in Macrophages and Mice with Conditional Ezh2 Deletion with LysM-Cre System

Kunanopparat

Leelahavanichkul

Visitchanakun

et al. 2023

IJMS

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“…The same modifications of histone 3 were present in immune relevant gene locations in myeloid cells of humans and mice after induction of trained immunity [ 8 , 9 , 40 ]. The H3K27ac, H3K4me1 and H3K4me3 modifications were involved in the enhanced immune response in beta glucan-trained murine macrophages [ 10 ], while H3K4me3 and H3K27me3 histone modifications are associated with epigenetic regulation of human immune related genes [ 13 ]. In the current study, increased modifications of H3H3K4me1, H3K4me3 and H3K27ac and decreased modifications of H3K27me3 affected multiple pathways associated with bacterial phagocytosis by channel catfish myeloid cells.…”

Section: Discussionmentioning

confidence: 99%

“…Trained immunity in mice results from epigenetic reprogramming of monocytes and macrophages through acetylation or methylation of specific lysines in the histone-H3 [ 8 , 9 ]. These changes occur at promoter regions H3K4me3 [ 8 , 10 , 11 ], and H3K27ac [ 9 , 10 , 12 ], enhancer regions H3K4me1 [ 10 , 13 ] and polychrome repression or gene silencing H3K27me3 [ 14 ]. Beta glucan exposure can induce these modifications in mammals, via the dectin-1 receptor [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Trained Immunity Provides Long-Term Protection against Bacterial Infections in Channel Catfish

Petrie‐Hanson¹,

Peterman²

2022

Pathogens

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Beta glucan exposure induced trained immunity in channel catfish that conferred long-term protection against Edwardsiella ictaluri and Edwardsiella piscicida infections one month post exposure. Flow cytometric analyses demonstrated that isolated macrophages and neutrophils phagocytosed higher amounts of E. ictaluri and E. piscicida. Beta glucan induced changes in the distribution of histone modifications in the monomethylation and trimethylation of H3K4 and modifications in the acetylation and trimethylation of H3K27. KEGG pathway analyses revealed that these modifications affected expressions of genes controlling phagocytosis, phagosome functions and enhanced immune cell signaling. These analyses correlate the histone modifications with gene functions and to the observed enhanced phagocytosis and to the increased survival following bacterial challenge in channel catfish. These data suggest the chromatin reconfiguration that directs trained immunity as demonstrated in mammals also occurs in channel catfish. Understanding the mechanisms underlying trained immunity can help us design prophylactic and non-antibiotic based therapies and develop broad-based vaccines to limit bacterial disease outbreaks in catfish production.

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“…Lysine methylation, a key, dynamic posttranslational modification that regulates protein stability and function, is regulated by lysine methyltransferase and lysine demethylase (95)(96)(97)(98). The abnormal expression of methyltransferase in many tumor types has been proven to be related to tumorigenesis and development, which has become the focus of anticancer research (98)(99)(100).…”

Section: Other Modificationsmentioning

confidence: 99%

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

et al. 2022

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Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Over 30 targeted inhibitors currently in preclinical and clinical trials have significant inhibitory effects on various tumors, including acute myelogenous leukemia (AML), diffuse large B cell lymphoma, prostate cancer, breast cancer and so on. However, resistance frequently occurs, revealing the limitations of BET inhibitor (BETi) therapy and the complexity of the BRD4 expression mechanism and action pathway. Current studies believe that when the internal and external environmental conditions of cells change, tumor cells can directly modify proteins by posttranslational modifications (PTMs) without changing the original DNA sequence to change their functions, and epigenetic modifications can also be activated to form new heritable phenotypes in response to various environmental stresses. In fact, research is constantly being supplemented with regards to that the regulatory role of BRD4 in tumors is closely related to PTMs. At present, the PTMs of BRD4 mainly include ubiquitination and phosphorylation; the former mainly regulates the stability of the BRD4 protein and mediates BETi resistance, while the latter is related to the biological functions of BRD4, such as transcriptional regulation, cofactor recruitment, chromatin binding and so on. At the same time, other PTMs, such as hydroxylation, acetylation and methylation, also play various roles in BRD4 regulation. The diversity, complexity and reversibility of posttranslational modifications affect the structure, stability and biological function of the BRD4 protein and participate in the occurrence and development of tumors by regulating the expression of tumor-related genes and even become the core and undeniable mechanism. Therefore, targeting BRD4-related modification sites or enzymes may be an effective strategy for cancer prevention and treatment. This review summarizes the role of different BRD4 modification types, elucidates the pathogenesis in the corresponding cancers, provides a theoretical reference for identifying new targets and effective combination therapy strategies, and discusses the opportunities, barriers, and limitations of PTM-based therapies for future cancer treatment.

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Screening of compounds to identify novel epigenetic regulatory factors that affect innate immune memory in macrophages

Cited by 15 publications

References 51 publications

The Regulatory Roles of Ezh2 in Response to Lipopolysaccharide (LPS) in Macrophages and Mice with Conditional Ezh2 Deletion with LysM-Cre System

The Regulatory Roles of Ezh2 in Response to Lipopolysaccharide (LPS) in Macrophages and Mice with Conditional Ezh2 Deletion with LysM-Cre System

Trained Immunity Provides Long-Term Protection against Bacterial Infections in Channel Catfish

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

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