A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses.
A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses.
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DOI：
10.1016/j.immuni.2009.04.012
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发表时间：
2009-06-19
期刊：
影响因子：
32.4
通讯作者：
Strober, Warren
中科院分区：
文献类型：
--
作者：
Meng, Guangxun;Zhang, Fuping;Fuss, Ivan;Kitani, Atsushi;Strober, Warren
NLRP3基因的错义突变(CIAS1)与以IL-1β过度产生为特征的自身炎症性疾病有关。在这里，我们分析了携带与Muckle-Wells综合征相关的NLRP3点突变的敲入小鼠的免疫反应。我们发现，这类小鼠的抗原提呈细胞(APC)在缺乏β的情况下，在TLR配体的刺激下会产生大量的IL-1、ATP和IL-18。这可能是由于炎症体激活阈值降低，允许对没有ATP脉冲的少量TLR配体进入细胞做出反应。此外，NLRP3基因敲入(KI)小鼠表现出自发性和接触性皮肤炎症，其特征是中性粒细胞浸润和来自造血细胞的Th17显性反应。KI小鼠的炎症是由于APC过度产生IL-1β，从而增强Th17分化所致。这些结果表明，在自身炎症性疾病中，NLRP3突变导致炎症体过度激活，从而导致Th17显性信息。
Missense mutations of NLRP3 gene (CIAS1) are associated with autoinflammatory disorders characterized with excessive production of IL-1β. Here we analyzed the immune responses of knock-in mice carrying a point mutation of NLRP3 associated with Muckle-Wells Syndrome. We found that antigen presenting cells (APCs) from such mice produce massive amounts of IL-1β and IL-18 upon stimulation with TLR ligands in the absence of ATP. This is likely due to a diminished inflammasome activation threshold that allows a response to the small amount of TLR ligand entering the cell without ATP pulse. Moreover, the NLRP3 knock-in (KI) mice exhibited spontaneous and contactant-induced skin inflammation characterized by neutrophil infiltration and Th17-dominant response, which was originated from hematopoietic cells. The inflammation of KI mice was resulted from excess IL-1β production from APCs which augments Th17 differentitation. These results demonstrate that NLRP3 mutation leads to inflammasome hyper-activation and consequently Th17-dominant infammation in autoinflammatory diseases.
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