Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction.
Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction.
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DOI：
10.4049/jimmunol.1200662
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发表时间：
2012-10-01
期刊：
影响因子：
--
通讯作者：
Cohen PL
中科院分区：
文献类型：
--
作者：
Zizzo G;Hilliard BA;Monestier M;Cohen PL
Mer酪氨酸激酶（MerTK）是巨噬细胞凋亡细胞（AC）的主要受体。其功能损害促进自身免疫和动脉粥样硬化，而过度表达与癌症预后不良相关。然而，关于调节人类MerTK表达的机制知之甚少。我们发现MerTK在巨噬细胞亚群中的表达是异质性的，主要局限于抗炎的“M2c”（CD14+CD16+CD163+CD204+CD206+CD209−）细胞，由M-CSF或糖皮质激素分化。在循环的CD14brightCD16+单核细胞中也可检测到少量的MerTK+“m2c样”细胞。MerTK的表达水平随免疫环境的变化而变化，在M1和“M2a”巨噬细胞以及树突状细胞中受到抑制。值得注意的是，虽然糖皮质激素诱导的分化与IL-10无关，但m - csf驱动的M2c极化和相关的MerTK上调需要IL-10。然而，无论是单独IL-10还是tgf - β都不足以完全分化M2c （CD16+CD163+MerTK+）巨噬细胞。因此，可能需要T淋巴细胞释放M-CSF和IL-10共同促进调节性T细胞介导的抗炎单核细胞-巨噬细胞的诱导。MerTK使M2c巨噬细胞比其他巨噬细胞亚群更有效地清除早期ACs，并介导CD14brightCD16+单核细胞清除AC。此外，M2c细胞释放Gas6，进而通过MerTK放大IL-10的分泌。因此，il -10依赖性诱导的Gas6/MerTK通路可能构成M2c巨噬细胞稳态的正循环和维持抗炎条件的关键检查点。我们的发现为人类巨噬细胞极化提供了新的见解，并支持MerTK在巨噬细胞功能调节中的核心作用。诱导M2c极化可用于狼疮等疾病的治疗，其中AC清除缺陷有助于启动和延续病理过程。
Mer tyrosine kinase (MerTK) is a major macrophage apoptotic cell (AC) receptor. Its functional impairment promotes autoimmunity and atherosclerosis, while 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 immunological environment, being suppressed in M1 and “M2a” macrophages, and in dendritic cells. Remarkably, while glucocorticoid-induced differentiation is IL-10-independent, M-CSF-driven M2c polarization and related MerTK up-regulation require IL-10. However, neither IL-10 alone nor TGFβ 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 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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