PMID- 32601098
OWN - NLM
STAT- MEDLINE
DCOM- 20210322
LR  - 20231111
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 205
IP  - 4
DP  - 2020 Aug 15
TI  - Enhanced Expression of Catalase in Mitochondria Modulates NF-kappaB-Dependent Lung 
      Inflammation through Alteration of Metabolic Activity in Macrophages.
PG  - 1125-1134
LID - 10.4049/jimmunol.1900820 [doi]
AB  - NF-kappaB is a reduction-oxidation-sensitive transcription factor that plays a key 
      role in regulating the immune response. In these studies, we intended to 
      investigate the role of mitochondrial-derived reactive oxygen species in 
      regulating NF-kappaB activation by studying transgenic mice that overexpress 
      mitochondrial-targeted human catalase (mCAT). We treated wild-type (WT) and mCAT 
      mice with intratracheal instillation of Escherichia coli LPS and found that mCAT 
      mice had exaggerated NF-kappaB activation in the lungs, increased neutrophilic 
      alveolitis, and greater lung inflammation/injury compared with WT mice. 
      Additional studies using bone marrow chimeras revealed that this 
      hyperinflammatory phenotype was mediated by immune/inflammatory cells. 
      Mechanistic studies using bone marrow-derived macrophages (BMDMs) showed that LPS 
      treatment induced a sustained increase in NF-kappaB activation and expression of 
      NF-kappaB-dependent inflammatory mediators in mCAT BMDMs compared with WT BMDMs. 
      Further investigations showed that cytoplasmic, but not mitochondrial, hydrogen 
      peroxide levels were reduced in LPS-treated mCAT BMDMs. However, mCAT macrophages 
      exhibited increased glycolytic and oxidative metabolism, coupled with increased 
      ATP production and an increased intracellular NADH/NAD(+) ratio compared with 
      BMDMs from WT mice. Treatment of BMDMs with lactate increased the intracellular 
      NADH/NAD(+) ratio and upregulated NF-kappaB activation after LPS treatment, whereas 
      treatment with a potent inhibitor of the mitochondrial pyruvate carrier (UK5099) 
      decreased the NADH/NAD(+) ratio and reduced NF-kappaB activation. Taken together, 
      these findings point to an increased availability of reducing equivalents in the 
      form of NADH as an important mechanism by which metabolic activity modulates 
      inflammatory signaling through the NF-kappaB pathway.
CI  - Copyright (c) 2020 by The American Association of Immunologists, Inc.
FAU - Han, Wei
AU  - Han W
AD  - Division of Allergy, Pulmonary and Critical Care Medicine, Department of 
      Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
FAU - Fessel, Joshua P
AU  - Fessel JP
AD  - Division of Allergy, Pulmonary and Critical Care Medicine, Department of 
      Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
AD  - Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 
      37232.
FAU - Sherrill, Taylor
AU  - Sherrill T
AD  - Division of Allergy, Pulmonary and Critical Care Medicine, Department of 
      Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
FAU - Kocurek, Emily G
AU  - Kocurek EG
AD  - Division of Allergy, Pulmonary and Critical Care Medicine, Department of 
      Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
FAU - Yull, Fiona E
AU  - Yull FE
AUID- ORCID: 0000-0003-1636-7942
AD  - Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 
      37232.
AD  - Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, 
      Nashville, TN 37232.
FAU - Blackwell, Timothy S
AU  - Blackwell TS
AD  - Division of Allergy, Pulmonary and Critical Care Medicine, Department of 
      Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; 
      timothy.blackwell@vumc.org.
AD  - Department of Cell and Developmental Biology, Vanderbilt University Medical 
      Center, Nashville, TN 37232; and.
AD  - Department of Veterans Affairs Medical Center, Nashville, TN 37212.
LA  - eng
GR  - I01 BX002378/BX/BLRD VA/United States
GR  - R01 HL061419/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20200629
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (NF-kappa B)
RN  - 0 (Reactive Oxygen Species)
RN  - 0U46U6E8UK (NAD)
RN  - EC 1.11.1.6 (Catalase)
SB  - IM
MH  - Animals
MH  - Bone Marrow/metabolism
MH  - Catalase/*metabolism
MH  - Lung/metabolism
MH  - Macrophages/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Mitochondria/*metabolism
MH  - NAD/metabolism
MH  - NF-kappa B/*metabolism
MH  - Pneumonia/*metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/physiology
PMC - PMC7415609
MID - NIHMS1603539
EDAT- 2020/07/01 06:00
MHDA- 2021/03/23 06:00
PMCR- 2021/08/15
CRDT- 2020/07/01 06:00
PHST- 2019/07/17 00:00 [received]
PHST- 2020/06/08 00:00 [accepted]
PHST- 2020/07/01 06:00 [pubmed]
PHST- 2021/03/23 06:00 [medline]
PHST- 2020/07/01 06:00 [entrez]
PHST- 2021/08/15 00:00 [pmc-release]
AID - jimmunol.1900820 [pii]
AID - 10.4049/jimmunol.1900820 [doi]
PST - ppublish
SO  - J Immunol. 2020 Aug 15;205(4):1125-1134. doi: 10.4049/jimmunol.1900820. Epub 2020 
      Jun 29.