Cited by 198Neuroinflammation and Neurodegeneration MechanismsImmune cells in cancerInflammasome and immune disorders

Secreted protein lipocalin‐2 promotes microglial M1 polarization

Jang, Eunha, Lee, Shinrye, Kim, Jong‐Heon, Kim, Jae‐Hong, Seo, Jung‐Wan, Lee, Won‐Ha, Mori, Kiyoshi, Nakao, Kazuwa +1 more·2013·The FASEB Journal

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 50 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.—Jang, E., Lee, S., Kim, J.‐H., Kim, J.‐H., Seo, J.‐W., Lee, W.‐H., Mori, K., Nakao, K., Suk, K. Secreted protein lipocalin‐2 promotes microglial M1 polarization. FASEB J. 27, 1176–1190 (2013). www.fasebj.org

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Crossref · 10.1096/fj.12-222257

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  • M2 depletion caused an increase in the number and proportion of iNOS+ M1 cells.

    “M2 depletion caused an increase in the number and proportion of iNOS+ M1 cells (Fig. 5d and Supplementary Fig. 8g online), supporting previous findings of reciprocal regulation between M1 and M2 polarization and associated cytokines25, 26.”

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Authors
Jang, E., Lee, S., Kim, J., Kim, J., Seo, J., Lee, W., Mori, K., Nakao, K., & Suk, K.
Affiliations
  • Kyungpook National University (KR)
  • Kyoto University (JP)
Corresponding author
Suk, Kyoungho
Venue
The FASEB Journal
Publisher
Wiley
Published
2012-12-03
Volume
27
Issue
3
Pages
1176-1190
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
OpenAlex
W2168114040
Cited by
198
References
66
Citations by year
2026: 9 · 2025: 8 · 2024: 13 · 2023: 20 · 2022: 19 · 2021: 19 · 2020: 11 · 2019: 8 · 2018: 11 · 2017: 12 · 2016: 19 · 2015: 16 · 2014: 21 · 2013: 11
FWCI
7.72
Type
journal article
Language
en
Open access
closed
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed (publishedVersion)
Funders
Ministry of Education, Science and Technology (2012‐0009328, 2008‐04090)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
neutrophil gelatinase-associated lipocalin, microglial M1 polarization, microglial M2 polarization, macrophage polarization, neuroinflammation, STAT6 phosphorylation, IL-4 signaling, lipopolysaccharide, cognitive impairment, secreted proteins
MeSH terms
Lipocalin-2, Acute-Phase Proteins, Animals, Gene Expression Regulation, Humans, Inflammation, Lipopolysaccharides, Mice, Mutant Strains, Phosphorylation, Proto-Oncogene Proteins, Oncogene Proteins, Cell Polarity, Microglia, Jurkat Cells, STAT6 Transcription Factor, Mice, Lipocalins

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