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A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease
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; ho...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9497176/ https://www.ncbi.nlm.nih.gov/pubmed/36139421 http://dx.doi.org/10.3390/cells11182846 |
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author | Elfiky, Ahmed M. I. Hageman, Ishtu L. Becker, Marte A. J. Verhoeff, Jan Li Yim, Andrew Y. F. Joustra, Vincent W. Mulders, Lieven Fung, Ivan Rioja, Inmaculada Prinjha, Rab K. Smithers, Nicholas N. Furze, Rebecca C. Mander, Palwinder K. Bell, Matthew J. Buskens, Christianne J. D’Haens, Geert R. Wildenberg, Manon E. de Jonge, Wouter J. |
author_facet | Elfiky, Ahmed M. I. Hageman, Ishtu L. Becker, Marte A. J. Verhoeff, Jan Li Yim, Andrew Y. F. Joustra, Vincent W. Mulders, Lieven Fung, Ivan Rioja, Inmaculada Prinjha, Rab K. Smithers, Nicholas N. Furze, Rebecca C. Mander, Palwinder K. Bell, Matthew J. Buskens, Christianne J. D’Haens, Geert R. Wildenberg, Manon E. de Jonge, Wouter J. |
author_sort | Elfiky, Ahmed M. I. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9497176 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94971762022-09-23 A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease Elfiky, Ahmed M. I. Hageman, Ishtu L. Becker, Marte A. J. Verhoeff, Jan Li Yim, Andrew Y. F. Joustra, Vincent W. Mulders, Lieven Fung, Ivan Rioja, Inmaculada Prinjha, Rab K. Smithers, Nicholas N. Furze, Rebecca C. Mander, Palwinder K. Bell, Matthew J. Buskens, Christianne J. D’Haens, Geert R. Wildenberg, Manon E. de Jonge, Wouter J. Cells Article 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. MDPI 2022-09-12 /pmc/articles/PMC9497176/ /pubmed/36139421 http://dx.doi.org/10.3390/cells11182846 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Elfiky, Ahmed M. I. Hageman, Ishtu L. Becker, Marte A. J. Verhoeff, Jan Li Yim, Andrew Y. F. Joustra, Vincent W. Mulders, Lieven Fung, Ivan Rioja, Inmaculada Prinjha, Rab K. Smithers, Nicholas N. Furze, Rebecca C. Mander, Palwinder K. Bell, Matthew J. Buskens, Christianne J. D’Haens, Geert R. Wildenberg, Manon E. de Jonge, Wouter J. A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease |
title | A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease |
title_full | A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease |
title_fullStr | A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease |
title_full_unstemmed | A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease |
title_short | A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease |
title_sort | bet protein inhibitor targeting mononuclear myeloid cells affects specific inflammatory mediators and pathways in crohn’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9497176/ https://www.ncbi.nlm.nih.gov/pubmed/36139421 http://dx.doi.org/10.3390/cells11182846 |
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