Efficient clearance of early apoptotic cells by human macrophages requires “M2c” polarization and MerTK induction

By G. Zizzo, B. Hilliard, M. Monestier, P. Cohen. Journal of Immunology, 2012

595 citations recorded by the source corpus.

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.

Subfields: Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/7c43f837fa7d28816766a2d3aa379a70b0020efa

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Tamás Rőszer

Citations in the corpus

Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype (2016, result): “After incubation with apoptotic cardiomyocytes, we observed a higher efficiency of M2c to phagocyte apoptotic cells compared with M1 and M2a macrophages (Figure 5J and K ), as previously reported.(22) The efferocytosis capacity of M2a was increased after incubation with neutrophil supernatant or NGA”
Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms (2015, background): “They also have high capacity of apoptotic cell uptake [92].”
Macrophage Polarization in Physiological and Pathological Pregnancy (2019, background): “These cells secrete IL-10, TGF-β, CCL16, and CCL18 and play crucial roles in the phagocytosis of apoptotic cells process (12, 22).”
Macrophage phenotypes in atherosclerosis (2014, background): “They exhibit high expression levels of the Mer receptor tyrosine kinase (MerTK) providing them with high efferocytosis capacity (29, 30).”
The Role of Macrophage Phenotype in Vascularization of Tissue Engineering Scaffolds (2014, unknown): “While several studies have profiled the differences in gene expression between M1 and M2a macrophages [36], very few have quantified the amount of secreted proteins, the most relevant outcome of polarization, and few studies have addressed the M2c phenotype at all [10,83,84].”