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Cell-intrinsic Wnt4 ligand regulates mitochondrial oxidative phosphorylation in macrophages


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Tlili, Mouna; Acevedo Ospina, Hamlet Adolfo; Descoteaux, Albert ORCID logoORCID: https://orcid.org/0000-0002-0633-5309; Germain, Michel et Heinonen, Krista M. ORCID logoORCID: https://orcid.org/0000-0002-2410-4432 (2022). Cell-intrinsic Wnt4 ligand regulates mitochondrial oxidative phosphorylation in macrophages Journal of Biological Chemistry , vol. 298 , nº 102193. pp. 1-15. DOI: 10.1016/j.jbc.2022.102193.

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>Macrophages respond to their environment by adopting a predominantly inflammatory or anti-inflammatory profile, depending on the context. The polarization of the subsequent response is regulated by a combination of intrinsic and extrinsic signals and is associated with alterations in macrophage metabolism. Although macrophages are important producers of Wnt ligands, the role of Wnt signaling in regulating metabolic changes associated with macrophage polarization remains unclear. Wnt4 upregulation has been shown to be associated with tissue repair and suppression of age-associated inflammation, which led us to generate Wnt4-deficient bone marrow-derived macrophages (BMDMs) to investigate its role in metabolism. We show that loss of Wnt4 led to modified mitochondrial structure, enhanced oxidative phosphorylation, and depleted intracellular lipid reserves, as the cells depended on fatty acid oxidation to fuel their mitochondria. Further we found that enhanced lipolysis was dependent on protein kinase C (PKC)-mediated activation of lysosomal acid lipase in Wnt4-deficient BMDMs. Although not irreversible, these metabolic changes promoted parasite survival during infection with Leishmania donovani. In conclusion, our results indicate that enhanced macrophage fatty acid oxidation impairs the control of intracellular pathogens, such as Leishmania. We further suggest that Wnt4 may represent a potential target in atherosclerosis, which is characterized by lipid storage in macrophages leading to them becoming foam cells.

Type de document: Article
Mots-clés libres: BMDM; Leishmania; Wnt4 signaling; fatty acid oxidation; lipid droplet; macrophage
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 10 juill. 2022 14:00
Dernière modification: 03 févr. 2024 19:15
URI: https://espace.inrs.ca/id/eprint/12791

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