PMID- 35822617
OWN - NLM
STAT- MEDLINE
DCOM- 20220727
LR  - 20231014
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 11
DP  - 2022 Jul 13
TI  - HIF-1alpha induces glycolytic reprograming in tissue-resident alveolar macrophages to 
      promote cell survival during acute lung injury.
LID - 10.7554/eLife.77457 [doi]
LID - e77457
AB  - Cellular metabolism is a critical regulator of macrophage effector function. 
      Tissue-resident alveolar macrophages (TR-AMs) inhabit a unique niche marked by 
      high oxygen and low glucose. We have recently shown that in contrast to bone 
      marrow-derived macrophages (BMDMs), TR-AMs do not utilize glycolysis and instead 
      predominantly rely on mitochondrial function for their effector response. It is 
      not known how changes in local oxygen concentration that occur during conditions 
      such as acute respiratory distress syndrome (ARDS) might affect TR-AM metabolism 
      and function; however, ARDS is associated with progressive loss of TR-AMs, which 
      correlates with the severity of disease and mortality. Here, we demonstrate that 
      hypoxia robustly stabilizes HIF-1alpha in TR-AMs to promote a glycolytic phenotype. 
      Hypoxia altered TR-AM metabolite signatures, cytokine production, and decreased 
      their sensitivity to the inhibition of mitochondrial function. By contrast, 
      hypoxia had minimal effects on BMDM metabolism. The effects of hypoxia on TR-AMs 
      were mimicked by FG-4592, a HIF-1alpha stabilizer. Treatment with FG-4592 decreased 
      TR-AM death and attenuated acute lung injury in mice. These findings reveal the 
      importance of microenvironment in determining macrophage metabolic phenotype and 
      highlight the therapeutic potential in targeting cellular metabolism to improve 
      outcomes in diseases characterized by acute inflammation.
CI  - (c) 2022, Woods et al.
FAU - Woods, Parker S
AU  - Woods PS
AUID- ORCID: 0000-0002-9054-4196
AD  - Department of Medicine, Section of Pulmonary and Critical Care Medicine, The 
      University of Chicago, Chicago, United States.
FAU - Kimmig, Lucas M
AU  - Kimmig LM
AD  - Department of Medicine, Section of Pulmonary and Critical Care Medicine, The 
      University of Chicago, Chicago, United States.
FAU - Sun, Kaitlyn A
AU  - Sun KA
AD  - Department of Medicine, Section of Pulmonary and Critical Care Medicine, The 
      University of Chicago, Chicago, United States.
FAU - Meliton, Angelo Y
AU  - Meliton AY
AD  - Department of Medicine, Section of Pulmonary and Critical Care Medicine, The 
      University of Chicago, Chicago, United States.
FAU - Shamaa, Obada R
AU  - Shamaa OR
AD  - Department of Medicine, Section of Pulmonary and Critical Care Medicine, The 
      University of Chicago, Chicago, United States.
FAU - Tian, Yufeng
AU  - Tian Y
AD  - Department of Medicine, Section of Pulmonary and Critical Care Medicine, The 
      University of Chicago, Chicago, United States.
FAU - Cetin-Atalay, Rengul
AU  - Cetin-Atalay R
AD  - Department of Medicine, Section of Pulmonary and Critical Care Medicine, The 
      University of Chicago, Chicago, United States.
FAU - Sharp, Willard W
AU  - Sharp WW
AD  - Department of Medicine, Section of Emergency Medicine, The University of Chicago, 
      Chicago, United States.
FAU - Hamanaka, Robert B
AU  - Hamanaka RB
AUID- ORCID: 0000-0002-8909-356X
AD  - Department of Medicine, Section of Pulmonary and Critical Care Medicine, The 
      University of Chicago, Chicago, United States.
FAU - Mutlu, Gokhan M
AU  - Mutlu GM
AUID- ORCID: 0000-0002-2056-612X
AD  - Department of Medicine, Section of Pulmonary and Critical Care Medicine, The 
      University of Chicago, Chicago, United States.
LA  - eng
GR  - T32 HL007605/HL/NHLBI NIH HHS/United States
GR  - R01 HL151680/HL/NHLBI NIH HHS/United States
GR  - R01 HL133675/HL/NHLBI NIH HHS/United States
GR  - R01 ES015024/ES/NIEHS NIH HHS/United States
GR  - U01 ES026718/ES/NIEHS NIH HHS/United States
GR  - P01 HL144454/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 - 20220713
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - *Acute Lung Injury
MH  - Animals
MH  - Cell Survival
MH  - Glycolysis
MH  - Hypoxia/metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Macrophages, Alveolar/metabolism
MH  - Mice
MH  - Oxygen/metabolism
MH  - *Respiratory Distress Syndrome
PMC - PMC9323005
OTO - NOTNLM
OT  - ARDS
OT  - HIF
OT  - acute lung injury
OT  - cell biology
OT  - immunology
OT  - inflammation
OT  - macrophages
OT  - metabolism
OT  - mouse
COIS- PW, RH, GM has a pending patent on targeting tissue-resident alveolar macrophage 
      metabolism to prevent their death during ARDS. (ARCD.P0740US.P1/1001176943), LK, 
      KS, AM, OS, YT, RC, WS No competing interests declared
EDAT- 2022/07/14 06:00
MHDA- 2022/07/28 06:00
PMCR- 2022/07/13
CRDT- 2022/07/13 06:53
PHST- 2022/01/31 00:00 [received]
PHST- 2022/07/10 00:00 [accepted]
PHST- 2022/07/14 06:00 [pubmed]
PHST- 2022/07/28 06:00 [medline]
PHST- 2022/07/13 06:53 [entrez]
PHST- 2022/07/13 00:00 [pmc-release]
AID - 77457 [pii]
AID - 10.7554/eLife.77457 [doi]
PST - epublish
SO  - Elife. 2022 Jul 13;11:e77457. doi: 10.7554/eLife.77457.