Homeostasis-altering molecular processes as mechanisms of inflammasome activation
Homeostasis-altering molecular processes as mechanisms of inflammasome activation
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DOI：
10.1038/nri.2016.151
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发表时间：
2017-03-01
影响因子：
100.3
通讯作者：
Masters, Seth L.
中科院分区：
文献类型：
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作者：
Liston, Adrian;Masters, Seth L.
先天免疫系统使用一组独特的种系编码模式识别受体（PRR）来启动下游炎症级联反应。这种识别系统与适应性免疫系统形成鲜明对比，适应性免疫系统依赖于高度可变、随机生成的抗原受体。先天免疫系统依赖固定 PRR 的一个关键限制是它对快速进化的病原体的反应不灵活。我们对炎症小体激活的理解的最新进展表明，先天免疫系统也具有复杂的机制来响应没有固定 PRR 的病原体。这包括识别垂死细胞的碎片，称为危险相关分子模式 (DAMP)，它可以以与病原体相关分子模式 (PAMP) 类似的方式直接激活 PRR。与此不同的是，炎症体成分NLRP3（包含NOD、LRR和pyrin结构域的3）和pyrin的新数据表明，它们并不直接检测分子模式，而是充当信号整合器，能够检测细胞质稳态的扰动，例如由感染引发的扰动。监测这些扰动，我们称之为“稳态改变分子过程”（HAMP），为先天免疫系统检测进化上的新型感染的能力提供了强大的灵活性；然而，HAMP 感应也可能是导致慢性炎症疾病的无菌炎症的基础。
The innate immune system uses a distinct set of germline-encoded pattern recognition receptors (PRRs) to initiate downstream inflammatory cascades. This recognition system is in stark contrast to the adaptive immune system, which relies on highly variable, randomly generated antigen receptors. A key limitation of the innate immune system's reliance on fixed PRRs is its inflexibility in responding to rapidly evolving pathogens. Recent advances in our understanding of inflammasome activation suggest that the innate immune system also has sophisticated mechanisms for responding to pathogens for which there is no fixed PRR. This includes the recognition of debris from dying cells, known as danger-associated molecular patterns (DAMPs), which can directly activate PRRs in a similar manner to pathogen-associated molecular patterns (PAMPs). Distinct from this, emerging data for the inflammasome components NLRP3 (NOD-, LRR-and pyrin domain-containing 3) and pyrin suggest that they do not directly detect molecular patterns, but instead act as signal integrators that are capable of detecting perturbations in cytoplasmic homeostasis, for example, as initiated by infection. Monitoring these perturbations, which we term ` homeostasis-altering molecular processes' (HAMPs), provides potent flexibility in the capacity of the innate immune system to detect evolutionarily novel infections; however, HAMP sensing may also underlie the sterile inflammation that drives chronic inflammatory diseases.