The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Efficient Clearance of Early Apoptotic Cells by Human Macrophages Requires M2c Polarization and MerTK Induction
Open accessAbstract
Mer tyrosine kinase (MerTK) is a major macrophage apoptotic cell (AC) receptor. Its functional impairment promotes autoimmunity and atherosclerosis, whereas overexpression correlates with poor prognosis in cancer. However, little is known about mechanisms regulating MerTK expression in humans. We found that MerTK expression is heterogenous among macrophage subsets, being mostly restricted to anti-inflammatory M2c (CD14+CD16+CD163+CD204+CD206+CD209−) cells, differentiated by M-CSF or glucocorticoids. Small numbers of MerTK+ “M2c-like” cells are also detectable among circulating CD14brightCD16+ monocytes. MerTK expression levels adapt to changing immunologic environment, being suppressed in M1 and M2a macrophages and in dendritic cells. Remarkably, although glucocorticoid-induced differentiation is IL-10 independent, M-CSF–driven M2c polarization and related MerTK upregulation require IL-10. However, neither IL-10 alone nor TGF-β are sufficient to fully differentiate M2c (CD16+CD163+MerTK+) macrophages. M-CSF and IL-10, both released by T lymphocytes, may thus be required together to promote regulatory T cell–mediated induction of anti-inflammatory monocytes-macrophages. MerTK enables M2c macrophages to clear early ACs more efficiently than other macrophage subsets, and it mediates AC clearance by CD14brightCD16+ monocytes. Moreover, M2c cells release Gas6, which in turn amplifies IL-10 secretion via MerTK. IL-10–dependent induction of the Gas6/MerTK pathway may, therefore, constitute a positive loop for M2c macrophage homeostasis and a critical checkpoint for maintenance of anti-inflammatory conditions. Our findings give new insight into human macrophage polarization and favor a central role for MerTK in regulation of macrophage functions. Eliciting M2c polarization can have therapeutic utility for diseases such as lupus, in which a defective AC clearance contributes to initiate and perpetuate the pathological process.
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Cites
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189
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“of regulatory pathways in phagocytes and release of anti-inflammatory cytokines (1, 2).”
BackgroundPhagocytosis and clearance of apoptotic cells is mediated by MER
Scott, R. S., McMahon, E. J., Pop, S. M., Reap, E. A., Caricchio, R., Cohen, P. L., Earp, H. S., & Matsushima, G. K. (2001) · Nature · doi:10.1038/35075603 · Cited by 1,215
Codarri, L., Gyülvészi, G., Tosevski, V., Hesske, L., Fontana, A., Magnenat, L., Suter, T., & Becher, B. (2011) · Nature Immunology · doi:10.1038/ni.2027 · Cited by 1,191 · cited 1×
“From this perspective, production of M-CSF by Tregs might counterbalance the well-known production of GM-CSF by proinflammatory Th1 and Th17 lymphocytes (51), with strong and direct repercussions of the Treg versus Th17 balance on M-CSF versus GM-CSF macrophage differentiation.”
BackgroundSystematic validation of specific phenotypic markers for in vitro polarized human macrophages
Ambarus, C. A., Krausz, S., van Eijk, M., Hamann, J., Radstake, T. R. D. J., Reedquist, K. A., Tak, P. P., & Baeten, D. L. P. (2012) · Journal of Immunological Methods · doi:10.1016/j.jim.2011.10.013 · Cited by 411
PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance
Mukundan, L., Odegaard, J. I., Morel, C. R., Heredia, J. E., Mwangi, J. W., Ricardo-Gonzalez, R. R., Goh, Y. P. S., Eagle, A. R., Dunn, S. E., Awakuni, J. U. H., et al. (2009) · Nature Medicine · doi:10.1038/nm.2048 · Cited by 368
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Clearance of apoptotic and necrotic cells and its immunological consequences
Krysko, D. V., D’Herde, K., & Vandenabeele, P. (2006) · Apoptosis · doi:10.1007/s10495-006-9527-8 · Cited by 316
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Cited by
Macrophage plasticity, polarization, and function in health and disease
Shapouri‐Moghaddam, A., Mohammadian, S., Vazini, H., Taghadosi, M., Esmaeili, S., Mardani, F., Seifi, B., Mohammadi, A., Afshari, J. T., & Sahebkar, A. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26429 · Cited by 4,930
Macrophages in atherosclerosis: a dynamic balance
Moore, K. J., Sheedy, F. J., & Fisher, E. A. (2013) · Nature reviews. Immunology · doi:10.1038/nri3520 · Cited by 2,559
Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms
Rőszer, T. (2015) · Mediators of Inflammation · doi:10.1155/2015/816460 · Cited by 1,762
Implications of macrophage polarization in autoimmunity
Funes, S. C., Rios, M., Escobar‐Vera, J., & Kalergis, A. M. (2018) · Immunology · doi:10.1111/imm.12910 · Cited by 1,005
The role of macrophage phenotype in vascularization of tissue engineering scaffolds
Spiller, K. L., Anfang, R. R., Spiller, K. J., Ng, J., Nakazawa, K. R., Daulton, J. W., & Vunjak-Novakovic, G. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.02.012 · Cited by 948
Metadata
- Authors
- Zizzo, G., Hilliard, B. A., Monestier, M., & Cohen, P. L.
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-10-01
- Volume
- 189
- Issue
- 7
- Pages
- 3508-3520
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2144741217
- Cited by
- 646
- References
- 9
- FWCI
- 10.35
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Zizzo, G., Hilliard, B. A., Monestier, M., & Cohen, P. L. (2012). Efficient Clearance of Early Apoptotic Cells by Human Macrophages Requires M2c Polarization and MerTK Induction. The Journal of Immunology. https://doi.org/10.4049/jimmunol.1200662
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