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Foxp3 drives oxidative phosphorylation and protection from lipotoxicity.

ABSTRACT: Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid oxidation-fueled oxidative phosphorylation (OXPHOS). It is unclear why this form of metabolism is favored in Tregs and, more specifically, whether this program represents an adaptation to the environment and developmental cues or is "hardwired" by Foxp3. Here we show, using metabolic analysis and an unbiased mass spectroscopy-based proteomics approach, that Foxp3 is both necessary and sufficient to program Treg-increased respiratory capacity and Tregs' increased ability to utilize fatty acids to fuel oxidative phosphorylation. Foxp3 drives upregulation of components of all the electron transport complexes, increasing their activity and ATP generation by oxidative phosphorylation. Increased fatty acid ?-oxidation also results in selective protection of Foxp3+ cells from fatty acid-induced cell death. This observation may provide novel targets for modulating Treg function or selection therapeutically.

SUBMITTER: Howie D

PROVIDER: S-EPMC5291728 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Foxp3 drives oxidative phosphorylation and protection from lipotoxicity.

Howie Duncan D Cobbold Stephen Paul SP Adams Elizabeth E Ten Bokum Annemieke A Necula Andra Stefania AS Zhang Wei W Huang Honglei H Roberts David J DJ Thomas Benjamin B Hester Svenja S SS Vaux David J DJ Betz Alexander G AG Waldmann Herman H

JCI insight 20170209 3

Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid oxidation-fueled oxidative phosphorylation (OXPHOS). It is unclear why this form of metabolism is favored in Tregs and, more specifically, whether this program represents an adaptation to the environment and developmental cues or is "hardwired" by Foxp3. Here we show, using metabolic analysis and an unbiased mass spectroscopy-based proteomics approach, that Foxp3 is both necessary and sufficient to program Treg- ...[more]

PMID: 28194435

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Project description:OBJECTIVE:Alternative activation (M2) of adipose tissue resident macrophage (ATM) inhibits obesity-induced metabolic inflammation. The underlying mechanisms remain unclear. Recent studies have shown that dysregulated lipid homeostasis caused by increased lipolysis in white adipose tissue (WAT) in the obese state is a trigger of inflammatory responses. We investigated the role of M2 macrophages in lipotoxicity-induced inflammation. METHODS:We used microarray experiments to profile macrophage gene expression regulated by two M2 inducers, interleukin-4 (Il-4), and peroxisome proliferator-activated receptor delta/gamma (Ppar?/Ppar?) agonists. Functional validation studies were performed in bone marrow-derived macrophages and mice deprived of the signal transducer and activator of transcription 6 gene (Stat6; downstream effector of Il-4) or Ppar?/Ppar? genes (downstream effectors of Stat6). Palmitic acid (PA) and ?-adrenergic agonist were employed to induce macrophage lipid loading in vitro and in vivo, respectively. RESULTS:Profiling of genes regulated by Il-4 or Ppar?/Ppar? agonists reveals that alternative activation promotes the cell survival program, while inhibiting that of inflammation-related cell death. Deletion of Stat6 or Ppar?/Ppar? increases the susceptibility of macrophages to PA-induced cell death. NLR family pyrin domain containing 3 (Nlrp3) inflammasome activation by PA in the presence of lipopolysaccharide is also increased in Stat6-/- macrophages and to a lesser extent, in Ppar?/?-/- macrophages. In concert, ?-adrenergic agonist-induced lipolysis results in higher levels of cell death and inflammatory markers in ATMs derived from myeloid-specific Ppar?/?-/- or Stat6-/- mice. CONCLUSIONS:Our data suggest that ATM cell death is closely linked to metabolic inflammation. Within WAT where concentrations of free fatty acids fluctuate, M2 polarization regulated by the Stat6-Ppar axis enhances ATM's tolerance to lipid-mediated stress, thereby maintaining the homeostatic state.

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Foxp3 drives oxidative phosphorylation and protection from lipotoxicity.

Publications

Foxp3 drives oxidative phosphorylation and protection from lipotoxicity.

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