Lipocalin-2 abrogates epithelial cell cycle arrest by PPARγ inhibition

Lab Invest. 2018 Nov;98(11):1408-1422. doi: 10.1038/s41374-018-0098-4. Epub 2018 Aug 7.


Macrophage-epithelial cross-talk regulates cell cycle progression and represents an important factor in rescuing epithelial cells from cell cycle arrest in order to maintain a healthy epithelial phenotype. However, the underlying mechanisms are still not well defined. We provide evidence that macrophage-secreted lipocalin-2 (Lcn-2) plays a key role during this process. In a co-culture setup using cell cycle arrested NRK52e renal epithelial cells and primary bone marrow-derived macrophages, Lcn-2 restores proliferation through inhibition of peroxisome proliferator-activated receptor (PPAR)-γ. Lcn-2 overexpression in macrophages overcomes epithelial cell cycle arrest and enhances epithelial markers via megalin and the downstream activation of PI3K/Akt signalling pathway, whereas a knockdown of Lcn-2 in macrophages prevented this effect. Our results show that macrophage-secreting Lcn-2 is crucial in rescuing epithelial cells from cell cycle arrest and in promoting epithelial proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Line
  • Cell Proliferation*
  • Epithelial Cells / physiology*
  • Lipocalin-2 / physiology*
  • Low Density Lipoprotein Receptor-Related Protein-2 / metabolism
  • Macrophages / metabolism
  • PPAR gamma / metabolism*
  • Phenotype
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats, Sprague-Dawley


  • Lcn2 protein, rat
  • Lipocalin-2
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Lrp2 protein, rat
  • PPAR gamma
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt