Abandoning M1/M2 for a Network Model of Macrophage Function.
Abandoning M1/M2 for a Network Model of Macrophage Function.
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DOI：
10.1161/circresaha.116.309194
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发表时间：
2016-07-22
影响因子：
20.1
通讯作者：
Swirski FK
中科院分区：
文献类型：
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作者：
Nahrendorf M;Swirski FK
不管它是怎么产生的，现在的M1/M2模式有问题吗？首先，这个概念是一种体外构建，依赖于用一组确定的因素刺激培养中的巨噬细胞。一种观点认为，尽管过于简化，但这种体外构建仍然为思考体内生物学提供了有用的指导。这种观点的问题在于，巨噬细胞离开其天然环境并置于培养环境后会发生巨大变化：经过7天的孵育期，培养的小胶质细胞和腹膜巨噬细胞完全失去其组织特异性基因表达程序。从这些体外环境中得出任何结论都是忽略了一个显而易见的事实：它们是不同的细胞。支持M1/M2范式的第二个论点承认，这是一种体外构建，但坚持巨噬细胞谱（以M1和M2为两极）在体内确实存在。如果这是真的，那么了解一些关于M1和M2在体外的活性将是有用的，就像在体外的实验一样：还原论和标准化。撇开这种使用的明显局限性不谈，依赖M1/M2频谱模型仍然是一个危险的主张。首先，如上所述，巨噬细胞在培养中发生了巨大的变化，因此，可能不再像体内存在的任何东西。其次，光谱是根据某些属性的大小排序的数组（例如，考虑光谱）。一个频谱需要在两个极端之间架起桥梁的中间体。在巨噬细胞生物学中，我们几乎没有证据表明它是一个包罗万象的谱。我们确实有证据表明刺激依赖性激活巨噬细胞网络。例如，人类巨噬细胞的转录谱分析发现了一个广泛的转录库，挑战了M1/M2范式。用巨噬细胞集落刺激因子（M-CSF）或粒细胞巨噬细胞集落刺激因子（GM-CSF）体外培养人单核细胞，然后用各种刺激激活，显示出与M1/M2轴有相当大的偏差，这一发现应该与研究心血管疾病中巨噬细胞生物学的研究人员特别相关，因为游离脂肪酸和高密度脂蛋白分子在这些刺激中。40换句话说，巨噬细胞遇到与心血管疾病相关的刺激会产生M1/M2谱外的介质。需要强调的是，脱离M1/M2框架取决于刺激措施。人们想知道，除了已确定的九种极化状态外，还有多少其他极化状态存在于额外的刺激或从特定器官分离的巨噬细胞中（即，除了m - csf和gm - csf产生的单核细胞来源的巨噬细胞）。我们应该完全放弃M1/M2模式吗？除了已经提到的原因之外，简化的M1/M2模型可能会扼杀而不是促进发现。一个典型的实验可能涉及从两组不同的动脉粥样硬化小鼠的主动脉中分离巨噬细胞。调查人员可能会测量一盒文字记录
Regardless of how it arose, is there a problem with the current M1/M2 model? For one, the concept is an in vitro construction that relies on stimulating macrophages in culture with a defined set of factors. One view posits that, although an oversimplification, this in vitro construction nevertheless provides a useful guide for thinking about in vivo biology. The problem with this perspective is that macrophages taken out of their native environments and placed in culture change dramatically: after a 7-day incubation period, cultured microglia and peritoneal macrophages completely lose their tissue-specific gene expression programs. 39 To conclude anything from these in vitro settings is to ignore the obvious: these are different cells. A second argument in favor of the M1/M2 paradigm acknowledges that it is an in vitro construction but insists the macrophage spectrum, with M1 and M2 as its polarized extremes, does exist in vivo. If this is true, then knowing something about M1 versus M2 activity in vitro would be useful in the same ways that in vitro experiments are useful: reductionism and standardization. Setting aside the obvious limitations of such use, relying on the M1/M2 spectrum model remains a perilous proposition. First, as noted above, macrophages placed into culture change dramatically and, thus, may no longer resemble anything that exists in vivo. Second, a spectrum is an array ordered according to the magnitudes of certain properties (consider, eg, a spectrum of light). A spectrum requires intermediates that bridge the 2 extremes. In macrophage biology, we have little evidence for an all-encompassing spectrum. We do have evidence for a stimulus-dependent activation macrophage network. Transcriptional profiling of human macrophages, for example, identified a broad transcriptional repertoire that challenges the M1/M2 paradigm. In vitro culture of human monocytes with macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF), followed by activation with diverse stimuli, revealed considerable deviation from the M1/M2 axis, an insight that should be particularly relevant to investigators studying macrophage biology in cardiovascular disease because free fatty acids and high-density lipoprotein molecules were among such stimuli. 40 In other words, a macrophage encountering a stimulus relevant to cardiovascular disease produces mediators that lie outside the M1/M2 spectrum. What needs to be emphasized is that departure from the M1/M2 framework depends on the stimulus. One wonders how many other polarization states, beyond the nine that were identified, exist with additional stimuli or with macrophages isolated from specific organs (ie, beyond M-CSF–and GM-CSF–generated monocyte-derived macrophages).Should we abandon the M1/M2 paradigm altogether? Beyond the reasons already mentioned, the reductive M1/M2 model arguably stifles, rather than enables discovery. A typical experiment might involve profiling macrophages isolated from the aortas of 2 different groups of mice with atherosclerosis. The investigators might measure a cassette of transcripts that