Regulation and Function of the Caspase-1 in an Inflammatory Microenvironment.
Regulation and Function of the Caspase-1 in an Inflammatory Microenvironment.
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DOI：
10.1038/jid.2015.119
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Jamora C
中科院分区：
文献类型：
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作者：
Lee DJ;Du F;Chen SW;Nakasaki M;Rana I;Shih VFS;Hoffmann A;Jamora C
炎性小体是一种蛋白质复合物，在对有害刺激的炎症反应中起着关键作用，这种刺激破坏了组织的稳态状态。NLRP3炎性小体存在于类似伤口的环境中，由三种成分组成：NLRP3、适配蛋白ASC和caspase-1。有趣的是，虽然ASC水平没有波动，但caspase-1水平在生理和病理条件下都升高。尽管观察到仅仅提高caspase-1水平就足以诱导炎症，但关于控制其表达的机制的关键问题尚未探索。我们发现在炎症微环境中，caspase-1受NFκB调控。与这种关联一致的是，caspase-1活性的抑制与NFκB激活的消除对伤口愈合的影响相似。令人惊讶的是，抑制NFκB/caspase-1轴不仅会破坏伤口愈合程序的炎症期，还会损害皮肤上皮干细胞增殖期的刺激。这些数据为伤口愈合反应不同阶段之间复杂的相互作用提供了机制基础，其中免疫细胞的下游信号活动可以激发局部干细胞的扩增以促进组织修复。
The inflammasome is a complex of proteins that plays a critical role in mounting an inflammatory response in reply to a harmful stimulus that compromises the homeostatic state of the tissue. The NLRP3 inflammasome, which is found in a wound-like environment, is comprised of three components: the NLRP3, the adaptor protein ASC and caspase-1. Interestingly, while ASC levels do not fluctuate, caspase-1 levels are elevated in both physiological and pathological conditions. Despite the observation that merely raising caspase-1 levels is sufficient to induce inflammation, the crucial question regarding the mechanism governing its expression is unexplored. We find that in an inflammatory microenvironment, caspase-1 is regulated by NFκB. Consistent with this association, the inhibition of caspase-1 activity parallels the effects on wound-healing caused by the abrogation of NFκB activation. Surprisingly, not only does inhibition of the NFκB/caspase-1 axis disrupt the inflammatory phase of the wound-healing program, it also impairs the stimulation of cutaneous epithelial stem cells of the proliferative phase. These data provide a mechanistic basis for the complex interplay between different phases of the wound-healing response in which the downstream signaling activity of immune cells can kindle the amplification of local stem cells to advance tissue repair.