PMID- 37820788
OWN - NLM
STAT- MEDLINE
DCOM- 20240122
LR  - 20240507
IS  - 2352-345X (Electronic)
IS  - 2352-345X (Linking)
VI  - 17
IP  - 2
DP  - 2024
TI  - BRD4 Regulates Glycolysis-Dependent Nos2 Expression in Macrophages Upon H pylori 
      Infection.
PG  - 292-308.e1
LID - S2352-345X(23)00180-7 [pii]
LID - 10.1016/j.jcmgh.2023.10.001 [doi]
AB  - BACKGROUND & AIMS: Metabolic reprogramming is essential for the activation and 
      functions of macrophages, including bacterial killing and cytokine production. 
      Bromodomain-containing protein 4 (BRD4) has emerged as a critical regulator of 
      innate immune response. However, the potential role of BRD4 in the metabolic 
      reprogramming of macrophage activation upon Helicobacter pylori infection remains 
      unclear. METHODS: Bone marrow-derived macrophages (BMDMs) from wild-type (WT) and 
      Brd4-myeloid deletion conditional knockout (Brd4-CKO) mice were infected with H 
      pylori. RNA sequencing was performed to evaluate the differential gene expression 
      between WT and Brd4-deficient BMDMs upon infection. An in vivo model of H pylori 
      infection using WT and Brd4-CKO mice was used to confirm the role of BRD4 in 
      innate immune response to infection. RESULTS: Depletion of Brd4 in BMDMs showed 
      impaired H pylori-induced glycolysis. In addition, H pylori-induced expression of 
      glycolytic genes, including Slc2a1 and Hk2, was decreased in Brd4-deficient 
      BMDMs. BRD4 was recruited to the promoters of Slc2a1 and Hk2 via 
      hypoxia-inducible factor-1alpha, facilitating their expression. BRD4-mediated 
      glycolysis stabilized H pylori-induced nitric oxide synthase (Nos2) messenger RNA 
      to produce nitric oxide. The NO-mediated killing of H pylori decreased in 
      Brd4-deficient BMDMs, which was rescued by pyruvate. Furthermore, Brd4-CKO mice 
      infected with H pylori showed reduced gastric inflammation and increased H pylori 
      colonization with reduced inducible NO synthase expression in gastric 
      macrophages. CONCLUSIONS: Our study identified BRD4 as a key regulator of 
      hypoxia-inducible factor-1alpha-dependent glycolysis and macrophage activation. 
      Furthermore, we show a novel regulatory role of BRD4 in innate immunity through 
      glycolysis to stabilize Nos2 messenger RNA for NO production to eliminate H 
      pylori infection.
CI  - Copyright (c) 2024 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Modi, Nikita
AU  - Modi N
AD  - Department of Biochemistry, College of Liberal Arts & Sciences, University of 
      Illinois at Urbana-Champaign, Urbana, Illinois.
FAU - Chen, Yanheng
AU  - Chen Y
AD  - Department of Biochemistry, College of Liberal Arts & Sciences, University of 
      Illinois at Urbana-Champaign, Urbana, Illinois.
FAU - Dong, Xingchen
AU  - Dong X
AD  - Department of Biochemistry, College of Liberal Arts & Sciences, University of 
      Illinois at Urbana-Champaign, Urbana, Illinois.
FAU - Hu, Xiangming
AU  - Hu X
AD  - Department of Biochemistry, College of Liberal Arts & Sciences, University of 
      Illinois at Urbana-Champaign, Urbana, Illinois.
FAU - Lau, Gee W
AU  - Lau GW
AD  - Department of Pathobiology, College of Veterinary Medicine, University of 
      Illinois at Urbana-Champaign, Urbana, Illinois.
FAU - Wilson, Keith T
AU  - Wilson KT
AD  - Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University 
      Medical Center, Nashville, Tennessee; Veterans Affairs Tennessee Valley 
      Healthcare System, Nashville, Tennessee.
FAU - Peek, Richard M Jr
AU  - Peek RM Jr
AD  - Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University 
      Medical Center, Nashville, Tennessee.
FAU - Chen, Lin-Feng
AU  - Chen LF
AD  - Department of Biochemistry, College of Liberal Arts & Sciences, University of 
      Illinois at Urbana-Champaign, Urbana, Illinois; Carl R. Woese Institute for 
      Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois. 
      Electronic address: lfchen@illinois.edu.
LA  - eng
GR  - R01 CA077955/CA/NCI NIH HHS/United States
GR  - P30 DK058404/DK/NIDDK NIH HHS/United States
GR  - P01 CA116087/CA/NCI NIH HHS/United States
GR  - I01 CX002171/CX/CSRD VA/United States
GR  - R01 DK058587/DK/NIDDK NIH HHS/United States
GR  - R01 CA281732/CA/NCI NIH HHS/United States
GR  - I01 CX002473/CX/CSRD VA/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231010
PL  - United States
TA  - Cell Mol Gastroenterol Hepatol
JT  - Cellular and molecular gastroenterology and hepatology
JID - 101648302
RN  - 0 (Nuclear Proteins)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - 0 (RNA, Messenger)
RN  - EC 1.14.13.39 (Nos2 protein, mouse)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
SB  - IM
CIN - Cell Mol Gastroenterol Hepatol. 2024;17(2):313-314. PMID: 38016647
MH  - Animals
MH  - Mice
MH  - Nuclear Proteins/genetics/metabolism
MH  - *Helicobacter Infections/microbiology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - *Helicobacter pylori/metabolism
MH  - Macrophages/metabolism
MH  - Nitric Oxide Synthase/metabolism
MH  - RNA, Messenger/metabolism
MH  - Glycolysis
MH  - Nitric Oxide Synthase Type II/metabolism
PMC - PMC10829522
OTO - NOTNLM
OT  - BRD4
OT  - Glycolysis
OT  - H pylori
OT  - HIF-1alpha
OT  - iNOS
EDAT- 2023/10/12 00:43
MHDA- 2024/01/22 06:41
PMCR- 2023/10/10
CRDT- 2023/10/11 19:36
PHST- 2023/05/09 00:00 [received]
PHST- 2023/10/03 00:00 [revised]
PHST- 2023/10/04 00:00 [accepted]
PHST- 2024/01/22 06:41 [medline]
PHST- 2023/10/12 00:43 [pubmed]
PHST- 2023/10/11 19:36 [entrez]
PHST- 2023/10/10 00:00 [pmc-release]
AID - S2352-345X(23)00180-7 [pii]
AID - 10.1016/j.jcmgh.2023.10.001 [doi]
PST - ppublish
SO  - Cell Mol Gastroenterol Hepatol. 2024;17(2):292-308.e1. doi: 
      10.1016/j.jcmgh.2023.10.001. Epub 2023 Oct 10.