SREBP1-induced fatty acid synthesis depletes macrophages antioxidant defences to promote their alternative activation
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Authors
Bidault, G
Virtue, S
Petkevicius, K
Jolin, HE
Dugourd, A
Guenantin, AC
Leggat, J
Mahler-Araujo, B
Lam, BYH
Ma, MK
Dale, M
Carobbio, S
Kaser, A
Fallon, PG
Saez Rodriguez, J
McKenzie, ANJ
Vidal-Puig, A
Publication Date
2021-09Journal Title
Nature Metabolism
ISSN
2522-5812
Publisher
Nature Research
Volume
3
Issue
9
Pages
1150-1162
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Bidault, G., Virtue, S., Petkevicius, K., Jolin, H., Dugourd, A., Guenantin, A., Leggat, J., et al. (2021). SREBP1-induced fatty acid synthesis depletes macrophages antioxidant defences to promote their alternative activation. Nature Metabolism, 3 (9), 1150-1162. https://doi.org/10.1038/s42255-021-00440-5
Abstract
Macrophages exhibit a spectrum of activation states ranging from classical to alternative activation1. Alternatively, activated macrophages are involved in diverse pathophysiological processes such as confining tissue parasites2, improving insulin sensitivity3 or promoting an immune tolerant microenvironment that facilitates tumour growth and metastasis4. Recently, the role of metabolism regulating macrophage function has come into focus as both the classical and alternative activation programmes require specific regulated metabolic reprogramming5. While most of the studies regarding immunometabolism have focussed on the catabolic pathways activated to provide energy, little is known about the anabolic pathways mediating macrophage alternative activation. In this study, we show that the anabolic transcription factor sterol regulatory element binding protein 1 (SREBP1) is activated in response to the canonical Th2 cytokine interleukin 4 (IL-4) to trigger the de novo lipogenesis (DNL) programme, as a necessary step for macrophage alternative activation. Mechanistically, DNL consumes NADPH, partitioning it away from cellular antioxidant defences and raising ROS levels. ROS serves as a second messenger, signalling sufficient DNL, and promoting macrophage alternative activation. The pathophysiological relevance of this mechanism is validated by showing that SREBP1/DNL is essential for macrophage alternative activation in vivo in a helminth infection model.
Sponsorship
This work was supported by the British Heart Foundation (RG/18/7/33636), the MRC (MC_UU_00014/2) and the FP7 MITIN (223450). K.P. was a recipient of a fellowship from the Wellcome Trust. A.N.J.M. and E.J. are supported by the Wellcome Trust (100963/Z/13/Z) and the MRC (U105178805). J.L. is a recipient fellowship of the British Heart Foundation. A.D. was a Marie-Curie Early-Stage Researcher supported by the European Union’s Horizon 2020 research and innovation programme (675585 Marie-Curie ITN ‘SymBioSys’) to J.S.-R. A.K. is supported by the Wellcome Trust (106260/Z/14/Z) and an ERC award (648889). P.F. is supported by the Science Foundation Ireland (10/IN.1/B3004). The IMS Genomics and Transcriptomics and Histology cores (B.M.-A., B.Y.H.L. and M.K.M.) are funded by the UK MRC Metabolic Disease Unit (MRC_MC_UU_12012/5) and a Wellcome Trust Strategic Award (100574/Z/12/Z). The Disease Model Core is part of the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5) and Wellcome Trust Strategic Award (100574/Z/12/Z).
Funder references
British Heart Foundation (None)
Wellcome Trust (100574/Z/12/Z)
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (106260/Z/14/Z)
European Commission (223450)
European Research Council (648889)
European Research Council (669879)
British Heart Foundation (RG/18/7/33636)
MRC (MC_UU_00014/2)
Medical Research Council (G0802051)
Medical Research Council (MC_G0802535)
Medical Research Council (G0400192)
Medical Research Council (MC_UU_12012/2)
Identifiers
PMC7611716, 34531575
External DOI: https://doi.org/10.1038/s42255-021-00440-5
This record's URL: https://www.repository.cam.ac.uk/handle/1810/329602
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