Lipocalin 2 is a regulator of macrophage polarization and NF-κB/STAT3 pathway activation

Mol Endocrinol. 2014 Oct;28(10):1616-28. doi: 10.1210/me.2014-1092. Epub 2014 Aug 15.


Lipocalin 2 (Lcn2) has been previously characterized as an adipokine/cytokine and implicated in obesity and inflammation. Herein, we investigated the role and potential mechanism of Lcn2 in the regulation of macrophage polarization in obesity-associated inflammation. We observed that Lcn2-/- mice displayed an up-regulation of expression of M1 macrophage marker Cd11c but a down-regulation of M2 marker arginase 1 in adipose tissue and liver of mice upon a high-fat diet feeding. Lcn2-deficient bone marrow-derived macrophages (BMDMs) were more sensitive to lipopolysaccharide (LPS) stimulation, leading to a more profound up-regulation of expression of pro-inflammatory markers than wild-type (WT) BMDMs. Accordingly, LPS stimulation elicited an increase in the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), c-Jun, and STAT3 signaling pathways as well as an up-regualtion of expression of NF-κB and STAT3 target genes such as IL-1β, IL-6, iNOS, and MCP-1 in Lcn2-/- BMDMs compared with WT controls. Pre-treatment of recombinant Lcn2 attenuated LPS-stimulated degradation of IκBα and STAT3 phosphorylation as well as LPS-induced gene expression of IL-6 and iNOS in Lcn2-/- BMDMs. Moreover, the NFκB inhibitor markedly blocked LPS-stimulated STAT3 phosphorylation in Lcn2-/- BMDMs. These results together with the time course of Lcn2 secretion, NFκB and STAT3 phosphorylation in response to LPS stimulation, suggest that Lcn2 plays a role as an anti-inflammatory regulator in macrophage activation via modulating a feed-forward activation of NFκB-STAT3 loop.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute-Phase Proteins / genetics
  • Acute-Phase Proteins / metabolism*
  • Adipose Tissue / metabolism
  • Animals
  • Arginase / metabolism
  • CD11c Antigen / metabolism
  • Cell Polarity / physiology*
  • Diet, High-Fat
  • Inflammation / metabolism
  • Lipocalin-2
  • Lipocalins / genetics
  • Lipocalins / metabolism*
  • Liver / metabolism
  • Macrophages / metabolism*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Obesity / metabolism
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Phosphorylation
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / physiology*


  • Acute-Phase Proteins
  • CD11c Antigen
  • Lipocalin-2
  • Lipocalins
  • NF-kappa B
  • Oncogene Proteins
  • STAT3 Transcription Factor
  • Lcn2 protein, mouse
  • Arg1 protein, mouse
  • Arginase