The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy
The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy
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DOI：
10.1016/j.molcel.2018.11.018
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发表时间：
2019-02-07
期刊：
影响因子：
16
通讯作者：
Chauhan, Santosh
中科院分区：
文献类型：
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作者：
Mehto, Subhash;Jena, Kautilya Kumar;Chauhan, Santosh
几项大规模的全基因组关联研究将IRGM与克罗恩病和其他炎症性疾病联系在一起，在这些疾病中，IRGM似乎具有保护功能。然而，IRGM实现这种抗炎作用的机制尚不清楚。在这里，我们揭示了IRGM/Irgm1是NLRP3炎症体激活的负调控因子。我们发现，由PAMPs、DAMPS和微生物增加的IRGM表达可以抑制由相同刺激引起的促炎反应。IRGM/Irgm1通过抑制NLRP3炎症小体的激活，负向调节IL-1β的成熟。从机制上，我们证明了IRGM与NLRP3和ASC相互作用，并通过阻止它们的寡聚来阻碍炎性小体的组装。此外，IRGM介导NLRP3和ASC的选择性自噬降解。通过抑制炎性小体的激活，IRGM/Irgm1在克罗恩病实验小鼠模型中保护免受热下垂和肠道炎症的影响。这项研究首次确定了IRGM预防炎症性疾病的机制。
Several large-scale genome-wide association studies genetically linked IRGM to Crohn's disease and other inflammatory disorders in which the IRGMappears to have a protective function. However, the mechanism by which IRGM accomplishes this anti-inflammatory role remains unclear. Here, we reveal that IRGM/Irgm1 is a negative regulator of the NLRP3 inflammasome activation. We show that IRGM expression, which is increased by PAMPs, DAMPs, and microbes, can suppress the pro-inflammatory responses provoked by the same stimuli. IRGM/Irgm1 negatively regulates IL-1 beta maturation by suppressing the activation of the NLRP3 inflammasome. Mechanistically, we show that IRGM interacts with NLRP3 and ASC and hinders inflammasome assembly by blocking their oligomerization. Further, IRGM mediates selective autophagic degradation of NLRP3 and ASC. By suppressing inflammasome activation, IRGM/Irgm1 protects from pyroptosis and gut inflammation in a Crohn's disease experimental mouse model. This study for the first time identifies the mechanism by which IRGM is protective against inflammatory disorders.