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KMID : 0620920230550071437
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Experimental & Molecular Medicine
2023 Volume.55 No. 7 p.1437 ~ p.1450
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Prolyl endopeptidase remodels macrophage function as a novel transcriptional coregulator and inhibits fibrosis
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Shuang-Zhe Lin
Wei-Jie Wu
Choi Seul-Ki
Jian-Bin Zhang
Dai-Xi Jiang
Chae Su-Mi
Wen-Jin Ding
Mingxi Liu
Yuan-Wen Chen
Jian-Gao Fan
Wei-Jie Wu
Yu-Qing Cheng
Jian-Bin Zhang
Dai-Xi Jiang
Tian-Yi Ren
Wen-Jin Ding
Mingxi Liu
Yuan-Wen Chen
Jian-Gao Fan
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Abstract
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Macrophages are immune cells crucial for host defense and homeostasis maintenance, and their dysregulation is involved in multiple pathological conditions, such as liver fibrosis. The transcriptional regulation in macrophage is indispensable for fine-tuning of macrophage functions, but the details have not been fully elucidated. Prolyl endopeptidase (PREP) is a dipeptidyl peptidase with both proteolytic and non-proteolytic functions. In this study, we found that Prep knockout significantly contributed to transcriptomic alterations in quiescent and M1/M2-polarized bone marrow-derived macrophages (BMDMs), as well as aggravated fibrosis in an experimental nonalcoholic steatohepatitis (NASH) model. Mechanistically, PREP predominantly localized to the macrophage nuclei and functioned as a transcriptional coregulator. Using CUT&Tag and co-immunoprecipitation, we found that PREP was mainly distributed in active cis-regulatory genomic regions and physically interacted with the transcription factor PU.1. Among PREP-regulated downstream genes, genes encoding profibrotic cathepsin B and D were overexpressed in BMDMs and fibrotic liver tissue. Our results indicate that PREP in macrophages functions as a transcriptional coregulator that finely tunes macrophage functions, and plays a protective role against liver fibrosis pathogenesis.
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KEYWORD
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Kupffer cells, Liver fibrosis, Transcriptional regulatory elements
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