title: Secreted protein lipocalin-2 promotes microglial M1 polarization.
abstract: Activated macrophages are classified into two different forms: classically activated (M1) or alternatively activated (M2) macrophages. The presence of M1/M2 phenotypic polarization has also been suggested for microglia. Here, we report that the secreted protein lipocalin 2 (LCN2) amplifies M1 polarization of activated microglia. LCN2 protein (EC 1 μg/ml), but not glutathione S-transferase used as a control, increased the M1-related gene expression in cultured mouse microglial cells after 8-24 h. LCN2 was secreted from M1-polarized, but not M2-polarized, microglia. LCN2 inhibited phosphorylation of STAT6 in IL-4-stimulated microglia, suggesting LCN2 suppression of the canonical M2 signaling. In the lipopolysaccharide (LPS)-induced mouse neuroinflammation model, the expression of LCN2 was notably increased in microglia. Primary microglial cultures derived from LCN2-deficient mice showed a suppressed M1 response and enhanced M2 response. Mice lacking LCN2 showed a markedly reduced M1-related gene expression in microglia after LPS injection, which was consistent with the results of histological analysis. Neuroinflammation-associated impairment in motor behavior and cognitive function was also attenuated in the LCN2-deficient mice, as determined by the rotarod performance test, fatigue test, open-field test, and object recognition task. These findings suggest that LCN2 is an M1-amplifier in brain microglial cells.
authors.affiliation: Department of Pharmacology, Kyungpook National University School of Medicine, 680 Gukchaebosang St., Joong-gu, Daegu 700-422, Korea.
authors.forename: Eunha
authors.initials: E
authors.lastname: Jang
authors.forename: Shinrye
authors.initials: S
authors.lastname: Lee
authors.forename: Jong-Heon
authors.initials: JH
authors.lastname: Kim
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.forename: Jung-Wan
authors.initials: JW
authors.lastname: Seo
authors.forename: Won-Ha
authors.initials: WH
authors.lastname: Lee
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008817:Mice, Mutant Strains; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D008070:Lipopolysaccharides; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; C071332:Lcn2 protein, mouse