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Acute iron deprivation reprograms human macrophage metabolism and reduces inflammation in vivo

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Title: Acute iron deprivation reprograms human macrophage metabolism and reduces inflammation in vivo
Authors: Pereira, M
Chen, T-D
Buang, N
Olona, A
Ko, J-H
Prendecki, M
Costa, ASH
Nikitopoulou, E
Tronci, L
Pusey, CD
Cook, HT
McAdoo, SP
Frezza, C
Behmoaras, J
Item Type: Journal Article
Abstract: Iron is an essential metal for fine-tuning the innate immune response through macrophage function. An integrative view of transcriptional and metabolic responses generated from iron perturbation in macrophages is lacking. Here we induced acute iron chelation in primary human macrophages and measured their transcriptional and metabolic responses by integrating RNA-sequencing and stable isotope tracing. We show that acute iron deprivation causes an anti-proliferative Warburg transcriptome characterized by an ATF4-dependent signature. Metabolically, iron-deprived human macrophages show an inhibition of oxidative phosphorylation and a concomitant increase in glycolysis, a large increase in glucosederived citrate pools associated with lipid droplet accumulation and modest levels of itaconate production. LPS polarization increases itaconate/succinate ratio and decreases pro-inflammatory cytokine production in iron-deprived macrophages. Acute iron deprivation reduces the severity of macrophage-dependent crescentic glomerulonephritis by limiting glomerular cell proliferation and inducing lipid accumulation in the renal cortex, phenocopying partly the iron-driven metabolic and transcriptional responses. These results suggest that acute iron deprivation has in vivo protective effects, by causing an antiinflammatory immuno-metabolic switch in macrophages.
Issue Date: 9-Jul-2019
Date of Acceptance: 21-May-2019
URI: http://hdl.handle.net/10044/1/70660
DOI: https://dx.doi.org/10.1016/j.celrep.2019.06.039
ISSN: 2211-1247
Publisher: Elsevier
Start Page: 498
End Page: 511.e5
Journal / Book Title: Cell Reports
Volume: 28
Issue: 2
Copyright Statement: ©2019 The Author(s).This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: MR/M004716/1
MR/N01121X/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
SUCCINATE-DEHYDROGENASE
CLUSTER BIOGENESIS
KEY ROLE
CELLS
MITOCHONDRIA
POLARIZATION
OXIDATION
ITACONATE
CITRATE
DAMAGE
glomerulonephritis
immunometabolism
inflammation
iron
macrophages
mitochondria
Publication Status: Published
Online Publication Date: 2019-07-09
Appears in Collections:Department of Immunology and Inflammation