Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy.
Immunology. 2013 Oct;140(2):179-90. doi: 10.1111/imm.12126.
Plasticity is a hallmark of macrophages, and in response to environmental signals these cells undergo different forms of polarized activation, the extremes of which are called classic (M1) and alternative (M2). Rapamycin (RAPA) is crucial for survival and functions of myeloid phagocytes, but its effects on macrophage polarization are not yet studied. To address this issue, human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon-γ or interleukin-4 (IL-4), respectively. The presence of RAPA (10 ng/ml) induced macrophage apoptosis in M2 but not in M1. Beyond the impact on survival in M2, RAPA reduced CXCR4, CD206 and CD209 expression and stem cell growth factor-β, CCL18 and CCL13 release. In contrast, in M1 RAPA increased CD86 and CCR7 expression and IL-6, tumour necrosis factor-α and IL-1β release but reduced CD206 and CD209 expression and IL-10, vascular endothelial growth factor and CCL18 release. In view of the in vitro data, we examined the in vivo effect of RAPA monotherapy (0·1 mg/kg/day) in 12 patients who were treated for at least 1 month before islet transplant. Cytokine release by Toll-like receptor 4-stimulated peripheral blood mononuclear cells showed a clear shift to an M1-like profile. Moreover, macrophage polarization 21 days after treatment showed a significant quantitative shift to M1. These results suggest a role of mammalian target of rapamycin (mTOR) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2-related diseases through mTOR inhibitor treatment.
可塑性是巨噬细胞的一个标志，这些细胞在环境信号的作用下经历不同形式的极化激活，其极端形式称为经典（M1）和替代（M2）。雷帕霉素（RAPA）对髓样吞噬细胞的存活和功能至关重要，但它对巨噬细胞极化的影响尚未得到研究。为了解决这个问题，从 6 名正常献血者获得的人巨噬细胞在体外通过脂多糖加干扰素-γ或白细胞介素-4（IL-4）分别极化到 M1 或 M2。10ng/ml 的 RAPA 在 M2 中诱导巨噬细胞凋亡，但在 M1 中不诱导。除了对 M2 中存活的影响外，RAPA 还降低了 CXCR4、CD206 和 CD209 的表达以及干细胞生长因子-β、CCL18 和 CCL13 的释放。相比之下，在 M1 中，RAPA 增加了 CD86 和 CCR7 的表达以及 IL-6、肿瘤坏死因子-α和 IL-1β的释放，但降低了 CD206 和 CD209 的表达以及 IL-10、血管内皮生长因子和 CCL18 的释放。鉴于体外数据，我们在 12 名接受胰岛移植前至少治疗 1 个月的患者中检查了 RAPA 单药治疗（0.1mg/kg/天）的体内效应。Toll 样受体 4 刺激的外周血单核细胞释放的细胞因子显示出向 M1 样表型的明显转变。此外，治疗后 21 天的巨噬细胞极化显示出向 M1 的显著数量转变。这些结果表明雷帕霉素靶蛋白（mTOR）在巨噬细胞极化的分子机制中起作用，并通过 mTOR 抑制剂治疗为人类 M2 相关疾病提出了新的治疗策略。
