Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals

Nat Commun. 2016 Oct 12:7:13130. doi: 10.1038/ncomms13130.

Abstract

Macrophages play crucial roles in host defence and tissue homoeostasis, processes in which both environmental stimuli and intracellularly generated metabolites influence activation of macrophages. Activated macrophages are classified into M1 and M2 macrophages. It remains unclear how intracellular nutrition sufficiency, especially for amino acid, influences on macrophage activation. Here we show that a lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with lysosomal vacuolar-type H+-ATPase (v-ATPase), and is the scaffold for amino acid-activated mTORC1 (mechanistic target of rapamycin complex 1), is critically required for M2 polarization. Lamtor1 deficiency, amino-acid starvation, or inhibition of v-ATPase and mTOR result in defective M2 polarization and enhanced M1 polarization. Furthermore, we identified liver X receptor (LXR) as the downstream target of Lamtor1 and mTORC1. Production of 25-hydroxycholesterol is dependent on Lamtor1 and mTORC1. Our findings demonstrate that Lamtor1 plays an essential role in M2 polarization, coupling immunity and metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / immunology
  • Amino Acids / deficiency
  • Amino Acids / immunology*
  • Animals
  • Cell Differentiation
  • Cell Lineage / immunology
  • Cytokines / genetics
  • Cytokines / immunology*
  • Female
  • Gene Expression Regulation
  • Liver X Receptors / genetics
  • Liver X Receptors / immunology
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Macrolides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / genetics*
  • Mechanistic Target of Rapamycin Complex 1 / immunology
  • Mice
  • Mice, Transgenic
  • Naphthyridines / pharmacology
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / immunology
  • Vacuolar Proton-Translocating ATPases / antagonists & inhibitors
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / immunology

Substances

  • 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
  • Adaptor Proteins, Signal Transducing
  • Amino Acids
  • Cytokines
  • Liver X Receptors
  • Macrolides
  • Naphthyridines
  • late endosome-lysosome membrane adaptor p18, mouse
  • concanamycin A
  • bafilomycin A1
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Vacuolar Proton-Translocating ATPases
  • Sirolimus