title: Lipocalin 2 is a regulator of macrophage polarization and NF-κB/STAT3 pathway activation.
abstract: 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.
authors.affiliation: Department of Food Science and Nutrition, University of Minnesota-Twin Cities, Saint Paul, Minnesota 55108.
authors.forename: Hong
authors.initials: H
authors.lastname: Guo
authors.forename: Daozhong
authors.initials: D
authors.lastname: Jin
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Chen
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001119:Arginase / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D016764:Cell Polarity / Q000502:physiology*; D059305:Diet, High-Fat; D007249:Inflammation / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000209:Acute-Phase Proteins; D039521:CD11c Antigen; D000071068:Lipocalin-2; D054834:Lipocalins; D016328:NF-kappa B; D015513:Oncogene Proteins; D050796:STAT3 Transcription Factor; C071332:Lcn2 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase