期刊
JOURNAL OF CROHNS & COLITIS
卷 16, 期 4, 页码 668-681出版社
OXFORD UNIV PRESS
DOI: 10.1093/ecco-jcc/jjab176
关键词
HDAC inhibitor; CES1; IBD
资金
- European Union [ITN-2014-EID-641665]
- Dutch Economic Affairs Top Sector Life Sciences & Health (LSH) -Top Consortia for Knowledge and Innovation's (TKI) [TKI-LSH T2017]
- European Crohn's and Colitis Organization (ECCO) Pioneer Grant, 2018
This study investigates the utility of ESM-tagged HDACi in inflammatory bowel disease (IBD) and finds that it can specifically target monocytes and inflammatory macrophages, showing potential therapeutic benefits in IBD.
Background and Aims Histone deacetylase inhibitors [HDACi] exert potent anti-inflammatory effects. Because of the ubiquitous expression of HDACs, clinical utility of HDACi is limited by off-target effects. Esterase-sensitive motif [ESM] technology aims to deliver ESM-conjugated compounds to human mononuclear myeloid cells, based on their expression of carboxylesterase 1 [CES1]. This study aims to investigate utility of an ESM-tagged HDACi in inflammatory bowel disease [IBD]. Methods CES1 expression was assessed in human blood, in vitro differentiated macrophage and dendritic cells, and Crohn's disease [CD] colon mucosa, by mass cytometry, quantitative polymerase chain reaction [PCR], and immunofluorescence staining, respectively. ESM-HDAC528 intracellular retention was evaluated by mass spectrometry. Clinical efficacy of ESM-HDAC528 was tested in dextran sulphate sodium [DSS]-induced colitis and T cell transfer colitis models using transgenic mice expressing human CES1 under the CD68 promoter. Results CES1 mRNA was highly expressed in human blood CD14(+) monocytes, in vitro differentiated and lipopolysaccharide [LPS]-stimulated macrophages, and dendritic cells. Specific hydrolysis and intracellular retention of ESM-HDAC528 in CES1(+) cells was demonstrated. ESM-HDAC528 inhibited LPS-stimulated IL-6 and TNF-alpha production 1000 times more potently than its control, HDAC800, in CES1(high) monocytes. In healthy donor peripheral blood, CES1 expression was significantly higher in CD14(++)CD16(-) monocytes compared with CD14(+)CD16(++) monocytes. In CD-inflamed colon, a higher number of mucosal CD68(+) macrophages expressed CES1 compared with non-inflamed mucosa. In vivo, ESM-HDAC528 reduced monocyte differentiation in the colon and significantly improved colitis in a T cell transfer model, while having limited potential in ameliorating DSS-induced colitis. Conclusions We demonstrate that monocytes and inflammatory macrophages specifically express CES1, and can be preferentially targeted by ESM-HDAC528 to achieve therapeutic benefit in IBD.
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