Aroylated phenylenediamine HO53 modulates innate immunity, histone acetylation and metabolism

Marjorie Laurence Barrier; Iwona Teresa Myszor; Priyanka Sahariah; Snaevar Sigurdsson; Miguel Carmena-Bargueño; Horacio Pérez-Sánchez; Gudmundur Hrafn Gudmundsson

doi:10.1016/j.molimm.2023.02.003

Aroylated phenylenediamine HO53 modulates innate immunity, histone acetylation and metabolism

Marjorie Laurence Barrier, Iwona Teresa Myszor, Priyanka Sahariah, Snaevar Sigurdsson, Miguel Carmena-Bargueño, Horacio Pérez-Sánchez, Gudmundur Hrafn Gudmundsson

University of Iceland

Research output: Contribution to journal › Article › peer-review

Abstract

In the current context of antibiotic resistance, the need to find alternative treatment strategies is urgent. Our research aimed to use synthetized aroylated phenylenediamines (APDs) to induce the expression of cathelicidin antimicrobial peptide gene (CAMP) to minimize the necessity of antibiotic use during infection. One of these compounds, HO53, showed promising results in inducing CAMP expression in bronchial epithelium cells (BCi-NS1.1 hereafter BCi). Thus, to decipher the cellular effects of HO53 on BCi cells, we performed RNA sequencing (RNAseq) analysis after 4, 8 and 24 h treatment of HO53. The number of differentially expressed transcripts pointed out an epigenetic modulation. Yet, the chemical structure and in silico modeling indicated HO53 as a histone deacetylase (HDAC) inhibitor. When exposed to a histone acetyl transferase (HAT) inhibitor, BCi cells showed a decreased expression of CAMP. Inversely, when treated with a specific HDAC3 inhibitor (RGFP996), BCi cells showed an increased expression of CAMP, indicating acetylation status in cells as determinant for the induction of the expression of the gene CAMP expression. Interestingly, a combination treatment with both HO53 and HDAC3 inhibitor RGFP966 leads to a further increase of CAMP expression. Moreover, HDAC3 inhibition by RGFP966 leads to increased expression of STAT3 and HIF1A, both previously demonstrated to be involved in pathways regulating CAMP expression. Importantly, HIF1α is considered as a master regulator in metabolism. A significant number of genes of metabolic enzymes were detected in our RNAseq data with enhanced expression conveying a shift toward enhanced glycolysis. Overall, we are demonstrating that HO53 might have a translational value against infections in the future through a mechanism leading to innate immunity strengthening involving HDAC inhibition and shifting the cells towards an immunometabolism, which further favors innate immunity activation.

Original language	English
Pages (from-to)	153-164
Number of pages	12
Journal	Molecular Immunology
Volume	155
DOIs	https://doi.org/10.1016/j.molimm.2023.02.003
Publication status	Published - Mar 2023

Bibliographical note

Funding Information: This project was supported by University of Iceland Research fund and Icelandic Center of Research (RANNÍS). The in silico research was funded by Fundación Séneca , Project 20988/PI/18. M.C.B. is a pre- doctoral employed to the training of research staff financed by the Plan Propio de Investigación de la UCAM. Supercomputing resources in this work were supported by the Plataforma Andaluza de Bioinformática of the University of Málaga , the supercomputing infrastructure of the NLHPC (ECM-02, Powered@NLHPC), and the Extremadura Research Centre for Advanced Technologies (CETA−CIEMAT), funded by the European Regional Development Fund ( ERDF ). CETA−CIEMAT is part of CIEMAT and the Government of Spain . Publisher Copyright: © 2023 The Authors

Other keywords

Acetylation
Aroylated Phenylenediamine
Cathelicidins
HDAC3
Histone Deacetylase Inhibitors/pharmacology
Histones/metabolism
Immunity, Innate
Immunometabolism
Innate Immunity
Phenylenediamines/pharmacology

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10.1016/j.molimm.2023.02.003

Cite this

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title = "Aroylated phenylenediamine HO53 modulates innate immunity, histone acetylation and metabolism",

abstract = "In the current context of antibiotic resistance, the need to find alternative treatment strategies is urgent. Our research aimed to use synthetized aroylated phenylenediamines (APDs) to induce the expression of cathelicidin antimicrobial peptide gene (CAMP) to minimize the necessity of antibiotic use during infection. One of these compounds, HO53, showed promising results in inducing CAMP expression in bronchial epithelium cells (BCi-NS1.1 hereafter BCi). Thus, to decipher the cellular effects of HO53 on BCi cells, we performed RNA sequencing (RNAseq) analysis after 4, 8 and 24 h treatment of HO53. The number of differentially expressed transcripts pointed out an epigenetic modulation. Yet, the chemical structure and in silico modeling indicated HO53 as a histone deacetylase (HDAC) inhibitor. When exposed to a histone acetyl transferase (HAT) inhibitor, BCi cells showed a decreased expression of CAMP. Inversely, when treated with a specific HDAC3 inhibitor (RGFP996), BCi cells showed an increased expression of CAMP, indicating acetylation status in cells as determinant for the induction of the expression of the gene CAMP expression. Interestingly, a combination treatment with both HO53 and HDAC3 inhibitor RGFP966 leads to a further increase of CAMP expression. Moreover, HDAC3 inhibition by RGFP966 leads to increased expression of STAT3 and HIF1A, both previously demonstrated to be involved in pathways regulating CAMP expression. Importantly, HIF1α is considered as a master regulator in metabolism. A significant number of genes of metabolic enzymes were detected in our RNAseq data with enhanced expression conveying a shift toward enhanced glycolysis. Overall, we are demonstrating that HO53 might have a translational value against infections in the future through a mechanism leading to innate immunity strengthening involving HDAC inhibition and shifting the cells towards an immunometabolism, which further favors innate immunity activation.",

keywords = "Acetylation, Aroylated Phenylenediamine, Cathelicidins, HDAC3, Histone Deacetylase Inhibitors/pharmacology, Histones/metabolism, Immunity, Innate, Immunometabolism, Innate Immunity, Phenylenediamines/pharmacology",

author = "Barrier, \{Marjorie Laurence\} and Myszor, \{Iwona Teresa\} and Priyanka Sahariah and Snaevar Sigurdsson and Miguel Carmena-Bargue{\~n}o and Horacio P{\'e}rez-S{\'a}nchez and Gudmundsson, \{Gudmundur Hrafn\}",

note = "Funding Information: This project was supported by University of Iceland Research fund and Icelandic Center of Research (RANN{\'I}S). The in silico research was funded by Fundaci{\'o}n S{\'e}neca , Project 20988/PI/18. M.C.B. is a pre- doctoral employed to the training of research staff financed by the Plan Propio de Investigaci{\'o}n de la UCAM. Supercomputing resources in this work were supported by the Plataforma Andaluza de Bioinform{\'a}tica of the University of M{\'a}laga , the supercomputing infrastructure of the NLHPC (ECM-02, Powered@NLHPC), and the Extremadura Research Centre for Advanced Technologies (CETA−CIEMAT), funded by the European Regional Development Fund ( ERDF ). CETA−CIEMAT is part of CIEMAT and the Government of Spain . Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = mar,

doi = "10.1016/j.molimm.2023.02.003",

language = "English",

volume = "155",

pages = "153--164",

journal = "Molecular Immunology",

issn = "0161-5890",

publisher = "Elsevier Ltd.",

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T1 - Aroylated phenylenediamine HO53 modulates innate immunity, histone acetylation and metabolism

AU - Barrier, Marjorie Laurence

AU - Myszor, Iwona Teresa

AU - Sahariah, Priyanka

AU - Sigurdsson, Snaevar

AU - Carmena-Bargueño, Miguel

AU - Pérez-Sánchez, Horacio

AU - Gudmundsson, Gudmundur Hrafn

N1 - Funding Information: This project was supported by University of Iceland Research fund and Icelandic Center of Research (RANNÍS). The in silico research was funded by Fundación Séneca , Project 20988/PI/18. M.C.B. is a pre- doctoral employed to the training of research staff financed by the Plan Propio de Investigación de la UCAM. Supercomputing resources in this work were supported by the Plataforma Andaluza de Bioinformática of the University of Málaga , the supercomputing infrastructure of the NLHPC (ECM-02, Powered@NLHPC), and the Extremadura Research Centre for Advanced Technologies (CETA−CIEMAT), funded by the European Regional Development Fund ( ERDF ). CETA−CIEMAT is part of CIEMAT and the Government of Spain . Publisher Copyright: © 2023 The Authors

PY - 2023/3

Y1 - 2023/3

N2 - In the current context of antibiotic resistance, the need to find alternative treatment strategies is urgent. Our research aimed to use synthetized aroylated phenylenediamines (APDs) to induce the expression of cathelicidin antimicrobial peptide gene (CAMP) to minimize the necessity of antibiotic use during infection. One of these compounds, HO53, showed promising results in inducing CAMP expression in bronchial epithelium cells (BCi-NS1.1 hereafter BCi). Thus, to decipher the cellular effects of HO53 on BCi cells, we performed RNA sequencing (RNAseq) analysis after 4, 8 and 24 h treatment of HO53. The number of differentially expressed transcripts pointed out an epigenetic modulation. Yet, the chemical structure and in silico modeling indicated HO53 as a histone deacetylase (HDAC) inhibitor. When exposed to a histone acetyl transferase (HAT) inhibitor, BCi cells showed a decreased expression of CAMP. Inversely, when treated with a specific HDAC3 inhibitor (RGFP996), BCi cells showed an increased expression of CAMP, indicating acetylation status in cells as determinant for the induction of the expression of the gene CAMP expression. Interestingly, a combination treatment with both HO53 and HDAC3 inhibitor RGFP966 leads to a further increase of CAMP expression. Moreover, HDAC3 inhibition by RGFP966 leads to increased expression of STAT3 and HIF1A, both previously demonstrated to be involved in pathways regulating CAMP expression. Importantly, HIF1α is considered as a master regulator in metabolism. A significant number of genes of metabolic enzymes were detected in our RNAseq data with enhanced expression conveying a shift toward enhanced glycolysis. Overall, we are demonstrating that HO53 might have a translational value against infections in the future through a mechanism leading to innate immunity strengthening involving HDAC inhibition and shifting the cells towards an immunometabolism, which further favors innate immunity activation.

AB - In the current context of antibiotic resistance, the need to find alternative treatment strategies is urgent. Our research aimed to use synthetized aroylated phenylenediamines (APDs) to induce the expression of cathelicidin antimicrobial peptide gene (CAMP) to minimize the necessity of antibiotic use during infection. One of these compounds, HO53, showed promising results in inducing CAMP expression in bronchial epithelium cells (BCi-NS1.1 hereafter BCi). Thus, to decipher the cellular effects of HO53 on BCi cells, we performed RNA sequencing (RNAseq) analysis after 4, 8 and 24 h treatment of HO53. The number of differentially expressed transcripts pointed out an epigenetic modulation. Yet, the chemical structure and in silico modeling indicated HO53 as a histone deacetylase (HDAC) inhibitor. When exposed to a histone acetyl transferase (HAT) inhibitor, BCi cells showed a decreased expression of CAMP. Inversely, when treated with a specific HDAC3 inhibitor (RGFP996), BCi cells showed an increased expression of CAMP, indicating acetylation status in cells as determinant for the induction of the expression of the gene CAMP expression. Interestingly, a combination treatment with both HO53 and HDAC3 inhibitor RGFP966 leads to a further increase of CAMP expression. Moreover, HDAC3 inhibition by RGFP966 leads to increased expression of STAT3 and HIF1A, both previously demonstrated to be involved in pathways regulating CAMP expression. Importantly, HIF1α is considered as a master regulator in metabolism. A significant number of genes of metabolic enzymes were detected in our RNAseq data with enhanced expression conveying a shift toward enhanced glycolysis. Overall, we are demonstrating that HO53 might have a translational value against infections in the future through a mechanism leading to innate immunity strengthening involving HDAC inhibition and shifting the cells towards an immunometabolism, which further favors innate immunity activation.

KW - Acetylation

KW - Aroylated Phenylenediamine

KW - Cathelicidins

KW - HDAC3

KW - Histone Deacetylase Inhibitors/pharmacology

KW - Histones/metabolism

KW - Immunity, Innate

KW - Immunometabolism

KW - Innate Immunity

KW - Phenylenediamines/pharmacology

UR - https://www.scopus.com/pages/publications/85148350839

U2 - 10.1016/j.molimm.2023.02.003

DO - 10.1016/j.molimm.2023.02.003

M3 - Article

C2 - 36812763

SN - 0161-5890

VL - 155

SP - 153

EP - 164

JO - Molecular Immunology

JF - Molecular Immunology

ER -

Aroylated phenylenediamine HO53 modulates innate immunity, histone acetylation and metabolism

Abstract

Bibliographical note

Other keywords

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