DNA 响应性的炎症小体及其在自身免疫中的调节剂。
DNA-responsive inflammasomes and their regulators in autoimmunity.
机构信息
Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P. O. Box 670056, Cincinnati, OH 45267, USA.
出版信息
Clin Immunol. 2012 Mar;142(3):223-31. doi: 10.1016/j.clim.2011.12.007. Epub 2011 Dec 29.
Abstract
Upon sensing microbial and self-derived DNA, DNA sensors initiate innate immune responses. These sensors include the interferon (IFN)-inducible Toll-like receptor 9 (TLR9) and PYHIN proteins. Upon sensing DNA, cytosolic (murine Aim2 and human AIM2) and nuclear (IFI16) PYHIN proteins recruit an adaptor protein (ASC) and pro-caspase-1 to form an inflammasome, which activates caspase-1. The activated caspase-1 cleaves pro-IL-1β and pro-IL-18 to generate active forms. However, upon sensing cytosolic DNA, the IFI16 protein recruits STING to induce the expression of type I IFN. Recognition of self DNA by innate immune cells contributes to the production of increased levels of type I IFN. Given that the type I IFNs modulate the expression of inflammasome proteins and that the IFN-inducible proteins inhibit the activity of DNA-responsive inflammasomes, an improved understanding of the molecular mechanisms that regulate the activity of DNA-responsive inflammasomes is likely to identify new therapeutic targets to treat autoimmune diseases.
摘要
当感知到微生物和自身衍生的 DNA 时，DNA 传感器会启动先天免疫反应。这些传感器包括干扰素（IFN）诱导的 Toll 样受体 9（TLR9）和 PYHIN 蛋白。在感知 DNA 后，细胞质（鼠 Aim2 和人 AIM2）和核（IFI16）PYHIN 蛋白募集衔接蛋白（ASC）和前胱天蛋白酶-1 形成炎症小体，激活胱天蛋白酶-1。激活的胱天蛋白酶-1 切割前 IL-1β 和前 IL-18 生成活性形式。然而，当感知细胞质 DNA 时，IFI16 蛋白募集 STING 诱导 I 型 IFN 的表达。先天免疫细胞识别自身 DNA 有助于增加 I 型 IFN 的产生水平。鉴于 I 型 IFNs 调节炎症小体蛋白的表达，IFN 诱导的蛋白抑制 DNA 反应性炎症小体的活性，因此，更好地了解调节 DNA 反应性炎症小体活性的分子机制可能会确定治疗自身免疫性疾病的新治疗靶点。
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