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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 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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“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.”
From M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination (2013) · cites this paper as [26]
Citations
Cites
Exploring the full spectrum of macrophage activation
Mosser, D. M., & Edwards, J. P. (2008) · Nature Reviews Immunology · doi:10.1038/nri2448 · Cited by 9,144
MANTOVANI, A., SOZZANI, S., LOCATI, M., ALLAVENA, P., & SICA, A. (2002) · Trends in Immunology · doi:10.1016/s1471-4906(02)02302-5 · Cited by 5,528
Protective and pathogenic functions of macrophage subsets
Murray, P. J., & Wynn, T. A. (2011) · Nature Reviews Immunology · doi:10.1038/nri3073 · Cited by 5,269
Monocyte and macrophage heterogeneity
Gordon, S., & Taylor, P. R. (2005) · Nature Reviews Immunology · doi:10.1038/nri1733 · Cited by 5,190
Microglia: Active sensor and versatile effector cells in the normal and pathologic brain
Hanisch, U.-K., & Kettenmann, H. (2007) · Nature Neuroscience · doi:10.1038/nn1997 · Cited by 3,676
Kettenmann, H., Hanisch, U.-K., Noda, M., & Verkhratsky, A. (2011) · Physiological Reviews · doi:10.1152/physrev.00011.2010 · Cited by 3,547
Development of Monocytes, Macrophages, and Dendritic Cells
Geissmann, F., Manz, M. G., Jung, S., Sieweke, M. H., Merad, M., & Ley, K. (2010) · Science · doi:10.1126/science.1178331 · Cited by 3,049
Alternative Activation of Macrophages: An Immunologic Functional Perspective
Martinez, F. O., Helming, L., & Gordon, S. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132532 · Cited by 2,745
Transcriptional regulation of macrophage polarization: enabling diversity with identity
Lawrence, T., & Natoli, G. (2011) · Nature Reviews Immunology · doi:10.1038/nri3088 · Cited by 2,284
Distinct role of macrophages in different tumor microenvironments
Lewis, C. E., & Pollard, J. W. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4005 · Cited by 2,225
Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration
Qin, L., Wu, X., Block, M. L., Liu, Y., Breese, G. R., Hong, J., Knapp, D. J., & Crews, F. T. (2007) · Glia · doi:10.1002/glia.20467 · Cited by 2,144
Kigerl, K. A., Gensel, J. C., Ankeny, D. P., Alexander, J. K., Donnelly, D. J., & Popovich, P. G. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3257-09.2009 · Cited by 2,130
Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron
Flo, T. H., Smith, K. D., Sato, S., Rodriguez, D. J., Holmes, M. A., Strong, R. K., Akira, S., & Aderem, A. (2004) · Nature · doi:10.1038/nature03104 · Cited by 1,877
Repertoire of microglial and macrophage responses after spinal cord injury
David, S., & Kroner, A. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3053 · Cited by 1,297
Altered macrophage differentiation and immune dysfunction in tumor development
Sica, A., & Bronte, V. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31422 · Cited by 1,258
Verreck, F. A. W., de Boer, T., Langenberg, D. M. L., Hoeve, M. A., Kramer, M., Vaisberg, E., Kastelein, R., Kolk, A. H. J., Malefyt, R. D. W., & Ottenhoff, T. H. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400983101 · Cited by 969
Mori, K., Lee, H. T., Rapoport, D., Drexler, I. R., Foster, K., Yang, J., Schmidt-Ott, K. M., Chen, X., Li, J. Y., Weiss, S., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23056 · Cited by 954
Self-citationBiochemical and functional characterization of three activated macrophage populations
Edwards, J. P., Zhang, X., Frauwirth, K. A., & Mosser, D. M. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.0406249 · Cited by 863
A Cell-Surface Receptor for Lipocalin 24p3 Selectively Mediates Apoptosis and Iron Uptake
Devireddy, L. R., Gazin, C., Zhu, X., & Green, M. R. (2005) · Cell · doi:10.1016/j.cell.2005.10.027 · Cited by 672
High‐yield isolation of murine microglia by mild trypsinization
Saura, J., Tusell, J. M., & Serratosa, J. (2003) · Glia · doi:10.1002/glia.10274 · Cited by 592
Neutrophil Gelatinase–Associated Lipocalin (NGAL) as a Marker of Kidney Damage
Bolignano, D., Donato, V., Coppolino, G., Campo, S., Buemi, A., Lacquaniti, A., & Buemi, M. (2008) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2008.01.020 · Cited by 591
Henry, C. J., Huang, Y., Wynne, A. M., & Godbout, J. P. (2009) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2008.09.002 · Cited by 565
Minagar, A., Shapshak, P., Fujimura, R. K., Ownby, R., Heyes, M., & Eisdorfer, C. (2002) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(02)00207-1 · Cited by 536
Koenigsknecht-Talboo, J., & Landreth, G. E. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1808-05.2005 · Cited by 477
On the delay-dependent involvement of the hippocampus in object recognition memory
HAMMOND, R. (2004) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2004.03.005 · Cited by 476
Comparison of polarization properties of human adult microglia and blood‐derived macrophages
Durafourt, B. A., Moore, C. S., Zammit, D., Johnson, T., Zaguia, F., Guiot, M., Bar‐Or, A., & Antel, J. P. (2012) · Glia · doi:10.1002/glia.22298 · Cited by 470
Nielsen, B. S., Borregaard, N., Bundgaard, J. R., Timshel, S., Sehested, M., & Kjeldsen, L. (1996) · Gut · doi:10.1136/gut.38.3.414 · Cited by 422
Michelucci, A., Heurtaux, T., Grandbarbe, L., Morga, E., & Heuschling, P. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.02.003 · Cited by 411
Human neutrophil gelatinase-associated lipocalin and homologous proteins in rat and mouse
Kjeldsen, L., Cowland, J. B., & Borregaard, N. (2000) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/s0167-4838(00)00152-7 · Cited by 368
Lipocalin 2 promotes breast cancer progression
Yang, J., Bielenberg, D. R., Rodig, S. J., Doiron, R., Clifton, M. C., Kung, A. L., Strong, R. K., Zurakowski, D., & Moses, M. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810617106 · Cited by 356
Cowland, J. B., Sørensen, O. E., Sehested, M., & Borregaard, N. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.12.6630 · Cited by 354
Signal transduction of inflammatory cytokines and tumor development
Yoshimura, A. (2006) · Cancer Science · doi:10.1111/j.1349-7006.2006.00197.x · Cited by 314
An inflammatory review of Parkinson's disease
Orr, C. F., Rowe, D. B., & Halliday, G. M. (2002) · Progress in Neurobiology · doi:10.1016/s0301-0082(02)00127-2 · Cited by 309
A new modality for immunosuppression: targeting the JAK/STAT pathway
O’Shea, J. J., Pesu, M., Borie, D. C., & Changelian, P. S. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1441 · Cited by 305
Lipocalin-2 Is an Autocrine Mediator of Reactive Astrocytosis
Lee, S., Park, J., Lee, W., Kim, H., Park, H., Mori, K., & Suk, K. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.5273-08.2009 · Cited by 286
Self-citationSchefer, V., & Talan, M. I. (1996) · Experimental Gerontology · doi:10.1016/0531-5565(95)02032-2 · Cited by 278
Raivich, G., & Banati, R. (2004) · Brain research. Brain research reviews · doi:10.1016/j.brainresrev.2004.06.006 · Cited by 263
Neutrophil gelatinase-associated lipocalin-mediated iron traffic in kidney epithelia
Schmidt-Ott, K. M., Mori, K., Kalandadze, A., Li, J.-Y., Paragas, N., Nicholas, T., Devarajan, P., & Barasch, J. (2006) · Current Opinion in Nephrology & Hypertension · doi:10.1097/01.mnh.0000232886.81142.58 · Cited by 237
Self-citationIsolation of murine microglial cells for RNA analysis or flow cytometry
Cardona, A. E., Huang, D., Sasse, M. E., & Ransohoff, R. M. (2006) · Nature Protocols · doi:10.1038/nprot.2006.327 · Cited by 236
IL-10–producing macrophages preferentially clear early apoptotic cells
Xu, W., Roos, A., Schlagwein, N., Woltman, A. M., Daha, M. R., & van Kooten, C. (2006) · Blood · doi:10.1182/blood-2005-10-4144 · Cited by 225
Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis
Sargsyan, S. A., Monk, P. N., & Shaw, P. J. (2005) · Glia · doi:10.1002/glia.20210 · Cited by 207
The Endogenous Estrogen Status Regulates Microglia Reactivity in Animal Models of Neuroinflammation
Vegeto, E., Belcredito, S., Ghisletti, S., Meda, C., Etteri, S., & Maggi, A. C. (2006) · Endocrinology · doi:10.1210/en.2005-1330 · Cited by 178
Dirscherl, K., Karlstetter, M., Ebert, S., Kraus, D., Hlawatsch, J., Walczak, Y., Moehle, C., Fuchshofer, R., & Langmann, T. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-3 · Cited by 175
Lipocalin-2 Is a Chemokine Inducer in the Central Nervous System
Lee, S., Kim, J., Kim, J., Seo, J.-W., Han, H. S., Lee, W., Mori, K., Nakao, K., Barasch, J. M., & Suk, K. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.299248 · Cited by 175
Self-citationA Dual Role of Lipocalin 2 in the Apoptosis and Deramification of Activated Microglia
Lee, S., Lee, J., Kim, S., Park, J., Lee, W., Mori, K., Kim, I. K., Kim, I. K., & Suk, K. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.5.3231 · Cited by 173
Self-citationMechanisms of microglia accumulation in Alzheimer’s disease: therapeutic implications
Khoury, J. E., & Luster, A. D. (2008) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2008.08.004 · Cited by 171
Choi, S., Langenbach, R. I., & Bosetti, F. (2007) · The FASEB Journal · doi:10.1096/fj.07-9411com · Cited by 159
Nairz, M., Theurl, I., Schroll, A., Theurl, M., Fritsche, G., Lindner, E., Seifert, M., Crouch, M.-L. V., Hantke, K., Akira, S., et al. (2009) · Blood · doi:10.1182/blood-2009-05-223354 · Cited by 146
Berard, J. L., Zarruk, J. G., Arbour, N., Prat, A., Yong, V. W., Jacques, F. H., Akira, S., & David, S. (2012) · Glia · doi:10.1002/glia.22342 · Cited by 136
Meheus, L., Fransen, L. M., Raymackers, J., Blockx, H., BEEUMEN, J. V., Bun, S. M. V., & VOORDE, A. V. D. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.151.3.1535 · Cited by 131
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Rathore, K. I., Berard, J. L., Redensek, A., Chierzi, S., López‐Vales, R., Santos, M. M., Akira, S., & David, S. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0116-11.2011 · Cited by 125
Increased plasma levels of lipocalin 2 in mild cognitive impairment
Choi, J., Lee, H., & Suk, K. (2011) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2011.03.023 · Cited by 123
Self-citationMacrophage Surface Expression of Annexins I and II in the Phagocytosis of Apoptotic Lymphocytes
Fan, X., Krahling, S., Smith, D. M., Williamson, P., & Schlegel, R. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-09-0670 · Cited by 123
Bruce‐Keller, A. J., Barger, S. W., Moss, N. I., Pham, J. T., Keller, J. N., & Nath, A. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00511.x · Cited by 121
Ip, J. P. K., Noçon, A. L., Hofer, M. J., Lim, S. L., Müller, M., & Campbell, I. L. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-124 · Cited by 115
β-Glucan Activates Microglia without Inducing Cytokine Production in Dectin-1-Dependent Manner
Shah, V. B., Huang, Y., Keshwara, R., Ozment-Skelton, T. R., Williams, D. L., & Keshvara, L. M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.5.2777 · Cited by 104
Acute endotoxemia is associated with upregulation of lipocalin 24p3/Lcn2 in lung and liver
Sunil, V. R., Patel, K. J., Nilsen‐Hamilton, M., Heck, D. E., Laskin, J. D., & Laskin, D. L. (2007) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2007.03.004 · Cited by 104
Scheffel, J., Regen, T., van Rossum, D., Seifert, S., Ribes, S., Nau, R., Parsa, R., Harris, R. A., Boddeke, H. W. G. M., Chuang, H., et al. (2012) · Glia · doi:10.1002/glia.22409 · Cited by 103
Park, S. Y., Lee, H., Hur, J., Kim, S. Y., Kim, H., Park, J.-H., Cha, S.-H., Kang, S. S., Cho, G. J., Choi, W. S., et al. (2002) · Molecular Brain Research · doi:10.1016/s0169-328x(02)00421-7 · Cited by 89
Self-citationBonow, R. H., Aïd, S., Zhang, Y., Becker, K. G., & Bosetti, F. (2008) · The Pharmacogenomics Journal · doi:10.1038/tpj.2008.15 · Cited by 73
Suh, H.-S., Zhao, M., Choi, N., Belbin, T. J., Brosnan, C. F., & Lee, S. C. (2009) · Virology · doi:10.1016/j.virol.2009.07.001 · Cited by 72
Self-citationMicroglia-Targeted Pharmacotherapy in Retinal Neurodegenerative Diseases
Schuetz, E., & Thanos, S. (2004) · Current Drug Targets · doi:10.2174/1389450043345164 · Cited by 65
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Kehrer, J. P. (2009) · Cell Biology and Toxicology · doi:10.1007/s10565-009-9119-9 · Cited by 62
Lee, S., Jang, E., Kim, J., Kim, J., Lee, W., & Suk, K. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.330662 · Cited by 42
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Jack, C. S., Arbour, N., Blain, M., Meier, U., Prat, A., & Antel, J. P. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181492a7 · Cited by 36
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Metadata
- 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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