Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage.
Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage.
复制标题
DOI：
10.1016/j.immuni.2015.08.008
复制
发表时间：
2015-09-15
期刊：
影响因子：
32.4
通讯作者：
O'Riordan MX
中科院分区：
文献类型：
--
作者：
Bronner DN;Abuaita BH;Chen X;Fitzgerald KA;Nuñez G;He Y;Yin XM;O'Riordan MX
内质网（ER）应激在许多人类疾病中都能观察到，且常常与炎症相关。内质网应激可通过核苷酸结合结构域和富含亮氨酸重复序列（NLRP3）炎症小体引发炎症，它可能通过与受损线粒体结合来刺激炎症小体的形成。内质网应激如何引发线粒体功能障碍和炎症小体激活尚不明确。在此我们利用一种感染模型表明，IRE1α内质网应激传感器通过一种不依赖ASC的、由NLRP3介导的前馈回路来调控线粒体功能障碍。IRE1α的激活增加了线粒体活性氧，促进了NLRP3与线粒体的结合。内质网应激诱导的半胱天冬酶 - 2和促凋亡因子Bid的切割需要NLRP3，这导致线粒体内容物的后续释放。半胱天冬酶 - 2和Bid对于感染相关或一般性内质网应激激活经典炎症小体是必需的。这些数据确定了一种依赖NLRP3 - 半胱天冬酶 - 2的机制，该机制将内质网应激传递给线粒体以促进炎症，整合了细胞应激和先天免疫。
Endoplasmic reticulum (ER) stress is observed in many human diseases, often associated with inflammation. ER stress can trigger inflammation through nucleotide-binding domain and leucine-rich repeat containing (NLRP3) inflammsome, which may stimulate inflammasome formation by association with damaged mitochondria. How ER stress triggers mitochondrial dysfunction and inflammasome activation is ill defined. Here we have used an infection model to show that the IRE1α ER stress sensor regulates regulated mitochondrial dysfunction through an NLRP3-mediated feed-forward loop, independently of ASC. IRE1α activation increased mitochondrial reactive oxygen species, promoting NLRP3 association with mitochondria. NLRP3 was required for ER stress-induced cleavage of caspase-2 and the pro-apoptotic factor, Bid, leading to subsequent release of mitochondrial contents. Caspase-2 and Bid were necessary for activation of the canonical inflammasome by infection-associated or general ER stress. These data identify an NLRP3-caspase-2 dependent mechanism that relays ER stress to the mitochondria to promote inflammation, integrating cellular stress and innate immunity.