PMID- 34029692
OWN - NLM
STAT- MEDLINE
DCOM- 20210819
LR  - 20211204
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 172
DP  - 2021 Aug 20
TI  - Advanced oxidation protein products impair autophagic flux in macrophage by 
      inducing lysosomal dysfunction via activation of PI3K-Akt-mTOR pathway in Crohn's 
      disease.
PG  - 33-47
LID - S0891-5849(21)00306-3 [pii]
LID - 10.1016/j.freeradbiomed.2021.05.018 [doi]
AB  - Dysfunction in macrophages is involved in the pathogenesis of various diseases, 
      including Crohn's disease (CD). Previously, we found that advanced oxidation 
      protein products (AOPPs) were predominantly deposited in macrophages in the 
      intestinal lamina propria of CD patients. However, whether AOPPs contributes to 
      macrophage dysfunction in CD and the underlying mechanism remains unknown. This 
      study aimed to investigate the effects of AOPPs on macrophages functions in CD. 
      In the present study, we discovered increased AOPPs levels were positively 
      correlated with impaired autophagy in macrophages of CD patients. AOPPs could 
      impair autophagic flux by inducing lysosomal dysfunction in RAW264.7 cell line 
      and macrophages in AOPPs-treated mice, evidenced by increased number of 
      autophagosomes, blocked degradation of autophagy-related proteins (LC3B-II and 
      SQSTM1/p62), and decreased activity of lysosomal proteolytic enzymes after AOPPs 
      challenge. Besides, AOPPs could also promote M1 polarization in RAW264.7 cells 
      and bone marrow derived macrophages (BMDMs) in AOPPs-treated mice. In addition, 
      our study revealed that PI3K-AKT-mTOR-TFEB pathway was activated by AOPPs in 
      macrophages. Inhibition of the PI3K pathway effectively alleviated AOPPs-induced 
      autophagy impairment and M1 polarization both in vitro and in vivo, thus reducing 
      intestinal inflammation in AOPPs-challenged mice. Together, this study 
      demonstrates that AOPPs-induced autophagy impairment in macrophages is crucial 
      for CD progression.
CI  - Copyright (c) 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Liao, Yan
AU  - Liao Y
AD  - Guangdong Provincial Key Laboratory of Gastroenterology, Department of 
      Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 
      Guangdong, 510515, China.
FAU - Xu, Jiahui
AU  - Xu J
AD  - Guangdong Provincial Key Laboratory of Gastroenterology, Department of 
      Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 
      Guangdong, 510515, China; Department of Gastroenterology, The Second Affiliated 
      Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, China.
FAU - Qin, Biyan
AU  - Qin B
AD  - Guangdong Provincial Key Laboratory of Gastroenterology, Department of 
      Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 
      Guangdong, 510515, China.
FAU - Shi, Jie
AU  - Shi J
AD  - Guangdong Provincial Key Laboratory of Gastroenterology, Department of 
      Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 
      Guangdong, 510515, China.
FAU - Qin, Caolitao
AU  - Qin C
AD  - Guangdong Provincial Key Laboratory of Gastroenterology, Department of 
      Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 
      Guangdong, 510515, China.
FAU - Xie, Fang
AU  - Xie F
AD  - Guangdong Provincial Key Laboratory of Gastroenterology, Department of 
      Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 
      Guangdong, 510515, China.
FAU - Ou, Shiyu
AU  - Ou S
AD  - Guangdong Provincial Key Laboratory of Gastroenterology, Department of 
      Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 
      Guangdong, 510515, China.
FAU - Tang, Jing
AU  - Tang J
AD  - Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical 
      University, Nanning, Guangxi, 530021, China.
FAU - Wang, Weidong
AU  - Wang W
AD  - Guangdong Provincial Key Laboratory of Gastroenterology, Department of 
      Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 
      Guangdong, 510515, China.
FAU - Wu, Fengfei
AU  - Wu F
AD  - Guangdong Provincial Key Laboratory of Gastroenterology, Department of 
      Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 
      Guangdong, 510515, China.
FAU - Bai, Lan
AU  - Bai L
AD  - Guangdong Provincial Key Laboratory of Gastroenterology, Department of 
      Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 
      Guangdong, 510515, China. Electronic address: bailan_99@yeah.net.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210521
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Advanced Oxidation Protein Products)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - *Advanced Oxidation Protein Products
MH  - Animals
MH  - Autophagy
MH  - *Crohn Disease
MH  - Humans
MH  - Lysosomes
MH  - Macrophages
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases/genetics
MH  - Proto-Oncogene Proteins c-akt/genetics
MH  - TOR Serine-Threonine Kinases/genetics
OTO - NOTNLM
OT  - Advanced oxidation protein products
OT  - Autophagy
OT  - Crohn's disease
OT  - M1 polarization
OT  - Macrophage
EDAT- 2021/05/25 06:00
MHDA- 2021/08/20 06:00
CRDT- 2021/05/24 20:24
PHST- 2021/02/23 00:00 [received]
PHST- 2021/04/26 00:00 [revised]
PHST- 2021/05/08 00:00 [accepted]
PHST- 2021/05/25 06:00 [pubmed]
PHST- 2021/08/20 06:00 [medline]
PHST- 2021/05/24 20:24 [entrez]
AID - S0891-5849(21)00306-3 [pii]
AID - 10.1016/j.freeradbiomed.2021.05.018 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2021 Aug 20;172:33-47. doi: 
      10.1016/j.freeradbiomed.2021.05.018. Epub 2021 May 21.