Activation of the IL-1β-Processing inflammasome is involved in contact hypersensitivity
Activation of the IL-1β-Processing inflammasome is involved in contact hypersensitivity
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DOI：
10.1038/sj.jid.5700819
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发表时间：
2007-08-01
影响因子：
6.5
通讯作者：
French, Lars E.
中科院分区：
文献类型：
--
作者：
Watanabe, Hideki;Gaide, Olivier;French, Lars E.
炎性小体是调节半胱天冬酶-1活化的胞质蛋白复合物，半胱天冬酶-1将促炎细胞因子IL-1 β和IL-18切割成其活性形式。炎性体由NACHT、LRR和pyrin（NALP）家族成员组成，充当危险信号的传感器，以及含有CARD结构域（ASC）的衔接蛋白凋亡相关斑点样蛋白，该结构域允许招募caspase-1在复合物中。在皮肤中，暴露于接触致敏剂（CS）如三硝基氯苯会引起称为接触性超敏反应（CHS）或湿疹的免疫反应。在这种迟发型超敏反应中，获得性免疫的有效引发取决于先天免疫系统的伴随激活，包括皮肤中的IL-1 β/IL-18激活。为了确定炎性小体是否有助于CHS，我们分析了其在体外和体内对CS的反应能力。我们在这里表明，炎症体的关键成分存在于人角质形成细胞中，CS如三硝基氯苯诱导caspase-1/ ASC依赖性IL-1 β和IL-18的加工和分泌。我们还表明，ASC-和NALP 3-缺陷小鼠显示CS反应受损。这些发现表明CS作为激活皮肤中炎性小体的危险信号，并揭示了NALP 3和ASC作为CHS中先天免疫调节剂的新作用。
The inflammasome is a cytosolic protein complex regulating the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-1 beta and IL-18 into their active form. The inflammasome is composed of a NACHT-, LRR- and pyrin (NALP) family member that acts as a sensor for danger signals and the adaptor protein apoptosisassociated speck-like protein containing a CARD domain (ASC), which allows the recruitment of caspase-1 in the complex. In the skin, exposure to contact sensitizers (CS) such as trinitro-chlorobenzene causes an immune response called contact hypersensitivity (CHS) or eczema. In this delayed-type hypersensitivity response, efficient priming of the adaptive immunity depends on the concomitant activation of the innate immune system, including IL-1 beta/IL-18 activation in the skin. To determine if the inflammasome contributes to CHS, we have analyzed its capacity to react to CS in vitro and in vivo. We show here that key components of the inflammasome are present in human keratinocytes and that CS like trinitro-chlorobenzene induce caspase-1/ ASC dependent IL-1 beta and IL-18 processing and secretion. We also show that ASC- and NALP3-deficient mice display an impaired response to CS. These findings suggest that CS act as danger signals that activate the inflammasome in the skin, and reveal a new role of NALP3 and ASC as regulators of innate immunity in CHS.