Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways
Abstract
Monocytes/macrophages are heterogeneous and versatile cells that could undergo their phenotypically/functionally dynamic switch in response to the microenvironment signals. Two major macrophage subpopulations with different functions which represent extreme of a continuum in a universe of activation states, including classically activated/inflammatory (M1) and alternatively activated/regenerative (M2) macrophages, have long been recognized. Emerging evidence through genetic or pharmacologic approaches has now been made in defining the actual fate in vivo and in vitro underlying M1 or M2-like polarized activation under physiological and pathological conditions. These cells are characterized by their expression of cell surface markers, secreted cytokines and chemokines, and transcription and epigenetic pathways. Here in this review, we shed new light on the contribution of several major signaling pathways and their modulators/targets involved in directing the macrophage plasticity and polarized function, assess the mechanisms of macrophage polarization by interacting endogenous cellular mechanisms and molecules associated with reciprocal skewing of macrophage polarization between the M1 and M2 states. The identification of mechanisms underlying functional polarization of macrophages into M1 or M2 cells might provide new insights into a basis for macrophage-centered diagnostic and therapeutic strategies for multiple diseases.
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Activation of signal transducer and activator of transcription (STAT) is the key signaling required for macrophage polarization.
“Though several signaling involved in M2 polarization including JAK/STAT, PI3K/Akt, and AMPK pathway, activation of signal transducer and activator of transcription (STAT) is the key signaling required for macrophage polarization 72, 73.”
From Nicotinamide phosphoribosyltransferase prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice (2024) · cites this paper as [73]
Cites
Obesity is associated with macrophage accumulation in adipose tissue
Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319246 · Cited by 10,041 · see citing works
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189 · see citing works
Obesity induces a phenotypic switch in adipose tissue macrophage polarization
Lumeng, C. N., Bodzin, J. L., & Saltiel, A. R. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29881 · Cited by 4,664 · see citing works
Macrophage plasticity and polarization in tissue repair and remodelling
Mantovani, A., Biswas, S. K., Galdiero, M. R., Sica, A., & Locati, M. (2013) · The Journal of Pathology · doi:10.1002/path.4133 · Cited by 2,384 · see citing works
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 · see citing works
the Immunological Genome Consortium, Gautier, E. L., Shay, T., Miller, J., Greter, M., Jakubzick, C., Ivanov, S., Helft, J., Chow, A., Elpek, K. G., et al. (2012) · Nature Immunology · doi:10.1038/ni.2419 · Cited by 1,972 · see citing works
Kang, K., Reilly, S. M., Karabacak, V., Gangl, M. R., Fitzgerald, K., Hatano, B., & Lee, C.-H. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.04.002 · Cited by 699 · see citing works
The Kinase Akt1 Controls Macrophage Response to Lipopolysaccharide by Regulating MicroRNAs
Androulidaki, A., Iliopoulos, D., Arranz, A., Doxaki, C., Schworer, S., Zacharioudaki, V., Margioris, A. N., Tsichlis, P. N., & Tsatsanis, C. (2009) · Immunity · doi:10.1016/j.immuni.2009.06.024 · Cited by 581 · see citing works
MicroRNA let-7c Regulates Macrophage Polarization
Banerjee, S., Xie, N., Cui, H., Tan, Z., Yang, S., Icyuz, M., Abraham, E., & Liu, G. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202496 · Cited by 320 · see citing works
Hall, C. J., Boyle, R. H., Astin, J. W., Flores, M. V., Oehlers, S. H., Sanderson, L. E., Ellett, F., Lieschke, G. J., Crosier, K. E., & Crosier, P. S. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.018 · Cited by 266 · see citing works
Secreted protein lipocalin‐2 promotes microglial M1 polarization
Jang, E., Lee, S., Kim, J., Kim, J., Seo, J., Lee, W., Mori, K., Nakao, K., & Suk, K. (2013) · The FASEB Journal · doi:10.1096/fj.12-222257 · Cited by 198 · see citing works
Wang, L.-W., Tu, Y.-F., Huang, C.-C., & Ho, C.-J. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-175 · Cited by 119 · see citing works
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Tan, H.-Y., Wang, N., Li, S., Hong, M., Wang, X., & Feng, Y. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/2795090 · Cited by 657 · see citing works
New insights into M1/M2 macrophages: key modulators in cancer progression
Liu, J., Geng, X., Hou, J., & Wu, G. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02089-2 · Cited by 501 · see citing works
Zhou, F., Mei, J., Han, X., Li, H., Yang, S., Wang, M., Chu, L., Qiao, H., & Tang, T. (2019) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.01.015 · Cited by 400 · see citing works
Sun, J., Furio, L., Mecheri, R., van der Does, A. M., Lundeberg, E., Saveanu, L., Chen, Y., van Endert, P., Agerberth, B., & Diana, J. (2015) · Immunity · doi:10.1016/j.immuni.2015.07.013 · Cited by 292 · see citing works
Li, M., Sun, X., Zhao, J., Xia, L., Li, J., Xu, M., Wang, B., Guo, H., Yu, C., Gao, Y., et al. (2020) · Cellular & Molecular Immunology · doi:10.1038/s41423-019-0279-0 · Cited by 225 · see citing works
Self-citationZhang, N., Wang, Z., & Zhao, Y. (2020) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2020.03.002 · Cited by 72 · see citing works
Chen, Y., Wang, T., Liang, F., Han, J., Lou, Z., Yu, Y., Li, J., Zhan, T., Gu, Y., Dong, L., et al. (2024) · Theranostics · doi:10.7150/thno.94482 · Cited by 56 · see citing works
Self-citationWang, N., Gao, J., Jia, M., Ma, X., Lei, Z., Da, F., Yan, F., Zhang, H., Zhou, Y., Li, M., et al. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000485776 · Cited by 42 · see citing works
Su, S.-B., Qin, S.-Y., Xian, X.-L., Huang, F.-F., Huang, Q.-L., ZhangDi, H.-J., & Jiang, H.-X. (2021) · Life Sciences · doi:10.1016/j.lfs.2020.118677 · Cited by 40 · see citing works
Noguchi, T., Katoh, H., Nomura, S., Okada, K., & Watanabe, M. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1342944 · Cited by 20 · see citing works
- Authors
- Zhou, D., Huang, C., Lin, Z., Zhan, S., Kong, L., Fang, C., & Li, J.
- Affiliations
- Anhui Medical University (CN)
- Corresponding author
- Li, Jun
- Venue
- Cellular Signalling
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 26
- Issue
- 2
- Pages
- 192-197
- ISSN
- 0898-6568 (ISSN-L)
- OpenAlex
- W2042207589
- Cited by
- 778
- References
- 12
- Citations by year
- 2026: 27 · 2025: 81 · 2024: 77 · 2023: 78 · 2022: 89 · 2021: 76 · 2020: 69 · 2019: 73 · 2018: 52 · 2017: 43 · 2016: 43 · 2015: 44 · 2014: 25
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cellular Signalling (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation of China (81072686, 81273526)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- macrophage polarization, M1 macrophages, M2 macrophages, macrophage plasticity, signaling pathways, cytokines and chemokines, epigenetic regulation, transcription factors, macrophage heterogeneity, inflammation, tissue regeneration
- MeSH terms
- Humans, Macrophages, Signal Transduction, Phosphatidylinositol 3-Kinases, JNK Mitogen-Activated Protein Kinases, STAT Transcription Factors, Proto-Oncogene Proteins c-akt, Receptors, Notch, Janus Kinases
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