TSC1 controls macrophage polarization to prevent inflammatory disease

Nat Commun. 2014 Sep 1;5:4696. doi: 10.1038/ncomms5696.

Abstract

Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses, but the mechanisms that regulate the macrophage polarization are poorly defined. Here we show that tuberous sclerosis complex 1 (TSC1) is a critical regulator of M1 and M2 phenotypes of macrophages. Mice with myeloid-specific deletion of TSC1 exhibit enhanced M1 response and spontaneously develop M1-related inflammatory disorders. However, TSC1-deficient mice are highly resistant to M2-polarized allergic asthma. Inhibition of the mammalian target of rapamycin (mTOR) fails to reverse the hypersensitive M1 response of TSC1-deficient macrophages, but efficiently rescues the defective M2 polarization. Deletion of mTOR also fails to reverse the enhanced inflammatory response of TSC1-deficient macrophages. Molecular studies indicate that TSC1 inhibits M1 polarization by suppressing the Ras GTPase-Raf1-MEK-ERK pathway in mTOR-independent manner, whereas TSC1 promotes M2 properties by mTOR-dependent CCAAT/enhancer-binding protein-β pathways. Overall, these findings define a key role for TSC1 in orchestrating macrophage polarization via mTOR-dependent and independent pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / genetics*
  • Asthma / immunology
  • Asthma / pathology
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / immunology
  • Cell Differentiation
  • Cell Lineage / immunology
  • Female
  • Gene Expression Regulation
  • MAP Kinase Signaling System
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-raf / genetics
  • Proto-Oncogene Proteins c-raf / immunology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / immunology
  • Tuberous Sclerosis / genetics*
  • Tuberous Sclerosis / immunology
  • Tuberous Sclerosis / pathology
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / immunology
  • ras GTPase-Activating Proteins / genetics
  • ras GTPase-Activating Proteins / immunology

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • Cebpb protein, mouse
  • TSC1 protein, human
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • ras GTPase-Activating Proteins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-raf

Supplementary concepts

  • Tuberous Sclerosis 1