PMID- 37394591
OWN - NLM
STAT- MEDLINE
DCOM- 20230803
LR  - 20230804
IS  - 2092-6413 (Electronic)
IS  - 1226-3613 (Print)
IS  - 1226-3613 (Linking)
VI  - 55
IP  - 7
DP  - 2023 Jul
TI  - Prolyl endopeptidase remodels macrophage function as a novel transcriptional 
      coregulator and inhibits fibrosis.
PG  - 1437-1450
LID - 10.1038/s12276-023-01027-8 [doi]
AB  - 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.
CI  - (c) 2023. The Author(s).
FAU - Lin, Shuang-Zhe
AU  - Lin SZ
AD  - Department of Gastroenterology, Xin Hua Hospital affiliated to Shanghai Jiao Tong 
      University School of Medicine, Shanghai, 200092, China.
FAU - Wu, Wei-Jie
AU  - Wu WJ
AD  - Department of Gastroenterology, Xin Hua Hospital affiliated to Shanghai Jiao Tong 
      University School of Medicine, Shanghai, 200092, China.
AD  - Gastrointestinal Endoscopy Center, Fujian Provincial Hospital South Branch, 
      Fuzhou, 350003, Fujian, China.
FAU - Cheng, Yu-Qing
AU  - Cheng YQ
AD  - Department of Gastroenterology, Xin Hua Hospital affiliated to Shanghai Jiao Tong 
      University School of Medicine, Shanghai, 200092, China.
FAU - Zhang, Jian-Bin
AU  - Zhang JB
AD  - Department of Gastroenterology, Xin Hua Hospital affiliated to Shanghai Jiao Tong 
      University School of Medicine, Shanghai, 200092, China.
FAU - Jiang, Dai-Xi
AU  - Jiang DX
AD  - Department of Gastroenterology, Xin Hua Hospital affiliated to Shanghai Jiao Tong 
      University School of Medicine, Shanghai, 200092, China.
AD  - State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National 
      Clinical Research Center for Infectious Diseases, Collaborative Innovation Center 
      for Diagnosis and Treatment of Infectious Diseases, The First Affiliated 
      Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 
      310058, Zhejiang, China.
FAU - Ren, Tian-Yi
AU  - Ren TY
AD  - Department of Gastroenterology, Xin Hua Hospital affiliated to Shanghai Jiao Tong 
      University School of Medicine, Shanghai, 200092, China.
AD  - Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, 
      200092, China.
FAU - Ding, Wen-Jin
AU  - Ding WJ
AD  - Department of Gastroenterology, Xin Hua Hospital affiliated to Shanghai Jiao Tong 
      University School of Medicine, Shanghai, 200092, China.
FAU - Liu, Mingxi
AU  - Liu M
AD  - State Key Laboratory of Reproductive Medicine, The Affiliated Taizhou People's 
      Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, 
      Nanjing Medical University, Nanjing, 211166, Jiangsu, China. 
      mingxi.liu@njmu.edu.cn.
FAU - Chen, Yuan-Wen
AU  - Chen YW
AD  - Department of Gastroenterology, Huadong Hospital Affiliated to Fudan University, 
      Shanghai, 200040, China. chenywhdgi@fudan.edu.cn.
AD  - Department of Gerontology, Huadong Hospital Affiliated to Fudan University, 
      Shanghai, 200040, China. chenywhdgi@fudan.edu.cn.
FAU - Fan, Jian-Gao
AU  - Fan JG
AD  - Department of Gastroenterology, Xin Hua Hospital affiliated to Shanghai Jiao Tong 
      University School of Medicine, Shanghai, 200092, China. 
      fanjiangao@xinhuamed.com.cn.
AD  - Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, 
      200092, China. fanjiangao@xinhuamed.com.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230703
PL  - United States
TA  - Exp Mol Med
JT  - Experimental & molecular medicine
JID - 9607880
RN  - EC 3.4.21.26 (Prolyl Oligopeptidases)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Prolyl Oligopeptidases
MH  - Macrophages
MH  - Fibrosis
MH  - *Non-alcoholic Fatty Liver Disease/pathology
MH  - Liver Cirrhosis/pathology
MH  - Mice, Inbred C57BL
PMC - PMC10394032
COIS- The authors declare no competing interests.
EDAT- 2023/07/03 00:41
MHDA- 2023/08/03 06:43
PMCR- 2023/07/03
CRDT- 2023/07/02 23:37
PHST- 2022/11/17 00:00 [received]
PHST- 2023/04/06 00:00 [accepted]
PHST- 2023/03/28 00:00 [revised]
PHST- 2023/08/03 06:43 [medline]
PHST- 2023/07/03 00:41 [pubmed]
PHST- 2023/07/02 23:37 [entrez]
PHST- 2023/07/03 00:00 [pmc-release]
AID - 10.1038/s12276-023-01027-8 [pii]
AID - 1027 [pii]
AID - 10.1038/s12276-023-01027-8 [doi]
PST - ppublish
SO  - Exp Mol Med. 2023 Jul;55(7):1437-1450. doi: 10.1038/s12276-023-01027-8. Epub 2023 
      Jul 3.