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Mammalian target of rapamycin complex 2 (mTORC2) negatively regulates Toll-like receptor 4-mediated inflammatory

Jonathan Brown1, Huizhi Wang, Jill Suttles

  • 1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.

The Journal of Biological Chemistry
|November 3, 2011
PubMed

Insights

Mammalian target of rapamycin complex 2 (mTORC2) regulates innate immunity. Loss of rictor, an mTORC2 component, causes hyperinflammation by impairing Akt-FoxO1 signaling, revealing a novel pathway in TLR-mediated responses.

Area of Science:

  • Immunology
  • Cellular signaling
  • Molecular biology

Background:

  • The PI3K pathway is crucial for inflammatory responses.
  • mTORC2's role in innate immunity is largely unknown.
  • mTORC2 influences Akt, a key PI3K signaling component.

Purpose of the Study:

  • To investigate the role of mTORC2 in innate immunity.
  • To elucidate the mechanism by which mTORC2 regulates inflammation.
  • To identify downstream targets of mTORC2 in immune cells.

Main Methods:

  • Utilized rictor-deficient mouse embryonic fibroblasts (MEFs).
  • Employed rictor knockdown in dendritic cells.
  • Stimulated cells with lipopolysaccharide (LPS).
  • Assessed Akt phosphorylation and kinase activity.
  • Analyzed FoxO1 phosphorylation, localization, and function.
  • Investigated the impact of FoxO1 manipulation on inflammatory phenotypes.

Main Results:

  • Rictor deficiency in MEFs and dendritic cells led to a hyperinflammatory phenotype upon LPS stimulation.
  • This phenotype was linked to impaired Akt signaling, characterized by reduced Akt phosphorylation and kinase activity.
  • Phosphorylation of FoxO1 was impaired in rictor-deficient cells, leading to increased nuclear FoxO1.
  • FoxO1 knockdown or deletion attenuated the hyperinflammatory response and inflammatory cytokine production.
  • These findings highlight a novel mTORC2-Akt-FoxO1 signaling axis in regulating innate immunity.

Conclusions:

  • mTORC2, through its component rictor, plays a critical role in controlling the innate inflammatory response.
  • The pathway involves mTORC2-mediated regulation of Akt, which in turn controls FoxO1 phosphorylation and nuclear localization.
  • This study identifies a novel mechanism by which mTORC2 influences Toll-like receptor (TLR)-mediated inflammation via the FoxO1 transcription factor.

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