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

Abstract

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.

• Authors: Ahmed M I Elfiky, Ishtu L Hageman, Marte A J Becker, Jan Verhoeff, Andrew Y F Li Yim, Vincent W Joustra, Lieven Mulders, Ivan Fung, Inmaculada Rioja, Rab K Prinjha, Nicholas N Smithers, Rebecca C Furze, Palwinder K Mander, Matthew J Bell, Christianne J Buskens, Geert R D'Haens, Manon E Wildenberg, Wouter J de Jonge
• Journal: Cells (Cells) Vol. 11 Issue 18 (09 12 2022) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 36139421 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Inflammation Mediators
• Interleukin-6
• NF-kappa B
• Tumor Necrosis Factor-alpha
• RNA
• Proto-Oncogene Proteins c-akt
• Carboxylic Ester Hydrolases

Topics

• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Carboxylic Ester Hydrolases
• Crohn Disease (drug therapy, metabolism)
• Humans
• Inflammation Mediators
• Interleukin-6
• Myeloid Cells (metabolism)
• NF-kappa B
• Proto-Oncogene Proteins c-akt
• RNA
• Tumor Necrosis Factor-alpha