Autophagy alleviates mitochondrial DAMP-induced acute lung injury by inhibiting NLRP3 inflammasome
Autophagy alleviates mitochondrial DAMP-induced acute lung injury by inhibiting NLRP3 inflammasome
复制标题
自噬通过抑制 NLRP3 胞浆体减轻线粒体 DAMP 诱导的急性肺损伤
DOI：
10.1016/j.lfs.2020.118833
复制
发表时间：
2021-01-15
期刊：
影响因子：
6.1
通讯作者：
Liu, Fen
中科院分区：
文献类型：
--
作者：
Peng, Wei;Peng, Fei;Liu, Fen
目的：急性肺损伤（acutelunginjury，ALI）是以肺泡巨噬细胞过度活化和不可控制的肺部炎症反应为特征的一种急性肺损伤.线粒体损伤相关分子模式（mitochondrialdamage-associatedmolecularpatterns，MTDs）是由线粒体破裂释放的损伤相关分子模式（damage-associatedmolecularpatterns，DAMPs）之一，可诱导炎症反应，参与ALI的发病机制。尽管自噬在炎症反应中起着关键作用，但其在MTD诱导的ALI中的作用却知之甚少。本研究从体内外两个方面研究了自噬对MTD诱导的ALI的影响。主要方法：通过尾静脉注射外源性MTD或直接用培养的肺泡巨噬细胞系处理，建立MTD诱导的ALI模型。雷帕霉素和3-MA用于体内和体外调节自噬。检测Caspase-1、IL-1 β及其前体的表达。抑制NLRP 3炎性小体的活化，寻找自噬减轻MTD诱导的ALI的候选靶点和潜在的分子途径。关键发现：经MTD治疗后，炎性细胞因子和NLRP 3炎性小体相关蛋白的表达水平在体外和体内逐渐增加。最重要的是，随着雷帕霉素增强自噬，在MTD诱导的小鼠模型中，所有炎症细胞因子的分泌、肺损伤水平和NLRP 3炎性小体相关蛋白的表达水平都大大降低。自噬增强可减轻MTD诱导的炎症和肺损伤。自噬可以通过抑制NLRP 3炎性体来减轻MTD诱导的ALI中的炎症，并且可能代表调节MTD诱导的炎症反应的治疗靶点。
Aim: Acute lung injury (ALI) is characterized by alveolar macrophage overactivation and uncontrolled pulmonary inflammation. Mitochondrial damage-associated molecular patterns (MTDs), one type of damage-associated molecular patterns (DAMPs) released from ruptured mitochondrial, can induce inflammation which participates in the pathogenesis of ALI. Despite the critical role of autophagy in inflammatory response, little is known about its function in MTDs-induced ALI. Herein we have studied how autophagy attenuates MTDs-induced ALI in vitro and in vivo.Main methods: Exogenous MTDs were injected into mice through tail vein injection or directly treated with cultured alveolar macrophage cell lines to construct MTDs-induced ALI models. Rapamycin and 3-MA were used to regulate autophagy in vivo and in vitro. The expressions of Caspase-1, IL-1 beta, and their precursor were measured. Inhibition the activation of NLRP3 inflammasome to discover the candidate targets and potential molecular pathways involved in autophagy mitigating the MTDs-induced ALI.Key findings: After treatment with MTDs the expression levels of inflammatory cytokines and NLRP3 inflammasome-associated proteins were gradually increased in vitro and in vivo. Most importantly, with autophagy enhanced by rapamycin, all the secretion of inflammation cytokine, the level of lung injury, and the expression level of NLRP3 inflammasome-associated proteins were greatly decreased in MTDs-induced mouse model. MTDs-induced inflammation and lung injury were alleviated by autophagy enhancement. Autophagy can function as an effective way to alleviate inflammation in MTDs-induced ALI by inhibiting NLRP3 inflammasome and may represent a therapeutic target in modulating MTDs-induced inflammatory response.