mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation

Science. 2017 Sep 8;357(6355):1014-1021. doi: 10.1126/science.aaj2155. Epub 2017 Aug 10.

Abstract

Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissue-restricted homeostasis remains poorly understood. Here, working with mouse models of inflammation, we found that mechanistic target of rapamycin (mTOR)-dependent metabolic adaptation was required at discrete locations. mTOR was dispensable for dendritic cell (DC) homeostasis in secondary lymphoid tissues but necessary to regulate cellular metabolism and accumulation of CD103+ DCs and alveolar macrophages in lung. Moreover, while numbers of mTOR-deficient lung CD11b+ DCs were not changed, they were metabolically reprogrammed to skew allergic inflammation from eosinophilic T helper cell 2 (TH2) to neutrophilic TH17 polarity. The mechanism for this change was independent of translational control but dependent on inflammatory DCs, which produced interleukin-23 and increased fatty acid oxidation. mTOR therefore mediates metabolic adaptation of APCs in distinct tissues, influencing the immunological character of allergic inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • Antigens, CD / metabolism
  • CD11b Antigen / genetics
  • CD11b Antigen / metabolism
  • Dendritic Cells / immunology*
  • Eosinophils / immunology
  • Fatty Acids / metabolism
  • Homeostasis*
  • Hypersensitivity / metabolism*
  • Inflammation / metabolism*
  • Integrin alpha Chains / metabolism
  • Interleukin-23 / metabolism
  • Lung / metabolism*
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / immunology
  • Oxidation-Reduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Th17 Cells / immunology
  • Th2 Cells / immunology

Substances

  • Antigens, CD
  • CD11b Antigen
  • Fatty Acids
  • Integrin alpha Chains
  • Interleukin-23
  • alpha E integrins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse