Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages

Nature. 2013 Mar 28;495(7442):524-8. doi: 10.1038/nature11930. Epub 2013 Mar 20.

Abstract

Macrophages consist of at least two subgroups, M1 and M2 (refs 1-3). Whereas M1 macrophages are proinflammatory and have a central role in host defence against bacterial and viral infections, M2 macrophages are associated with responses to anti-inflammatory reactions, helminth infection, tissue remodelling, fibrosis and tumour progression. Trib1 is an adaptor protein involved in protein degradation by interacting with COP1 ubiquitin ligase. Genome-wide association studies in humans have implicated TRIB1 in lipid metabolism. Here we show that Trib1 is critical for the differentiation of F4/80(+)MR(+) tissue-resident macrophages--that share characteristics with M2 macrophages (which we term M2-like macrophages)--and eosinophils but not for the differentiation of M1 myeloid cells. Trib1 deficiency results in a severe reduction of M2-like macrophages in various organs, including bone marrow, spleen, lung and adipose tissues. Aberrant expression of C/EBPα in Trib1-deficient bone marrow cells is responsible for the defects in macrophage differentiation. Unexpectedly, mice lacking Trib1 in haematopoietic cells show diminished adipose tissue mass accompanied by evidence of increased lipolysis, even when fed a normal diet. Supplementation of M2-like macrophages rescues the pathophysiology, indicating that a lack of these macrophages is the cause of lipolysis. In response to a high-fat diet, mice lacking Trib1 in haematopoietic cells develop hypertriglyceridaemia and insulin resistance, together with increased proinflammatory cytokine gene induction. Collectively, these results demonstrate that Trib1 is critical for adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue-resident M2-like macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / cytology*
  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology
  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism
  • Cell Count
  • Cell Cycle Proteins / deficiency
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation*
  • Cytokines / genetics
  • Diet, High-Fat / adverse effects
  • Eosinophils / cytology
  • Eosinophils / metabolism
  • Female
  • Hypertriglyceridemia / chemically induced
  • Hypertriglyceridemia / genetics
  • Inflammation Mediators / metabolism
  • Insulin Resistance / genetics
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipodystrophy / chemically induced
  • Lipodystrophy / metabolism
  • Lipodystrophy / pathology
  • Lipolysis
  • Lung / cytology
  • Macrophages / classification
  • Macrophages / cytology*
  • Macrophages / metabolism*
  • Male
  • Mice
  • Neutrophils / cytology
  • Neutrophils / metabolism
  • Organ Specificity
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Spleen / cytology
  • Ubiquitin / metabolism

Substances

  • CCAAT-Enhancer-Binding Protein-alpha
  • Cell Cycle Proteins
  • Cytokines
  • Inflammation Mediators
  • Intracellular Signaling Peptides and Proteins
  • TRB3 protein, mouse
  • Trib1 protein, mouse
  • Ubiquitin
  • tribbles 2 protein, mouse
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE43563