The Effect of PGC-1alpha-SIRT3 Pathway Activation on Pseudomonas aeruginosa Infection.
The Effect of PGC-1alpha-SIRT3 Pathway Activation on Pseudomonas aeruginosa Infection.
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DOI：
10.3390/pathogens11020116
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发表时间：
2022-01-19
期刊：
影响因子：
--
通讯作者：
Sadikot RT
中科院分区：
文献类型：
--
作者：
Maurice NM;Bedi B;Yuan Z;Lin KC;Goldberg JB;Hart CM;Bailey KL;Sadikot RT
铜绿假单胞菌肺部感染的先天免疫应答依赖于一个模式识别受体网络，包括细胞内炎性体复合物，它可以识别病原体和宿主来源的信号，随后促进下游炎症信号传导。目前的证据表明，炎症小体对细菌清除没有贡献，事实上，炎症小体激活失调对急性和慢性铜绿假单胞菌肺部感染是有害的。考虑到线粒体损伤信号在募集炎性小体信号中的作用，我们研究了线粒体靶向治疗是否可以减弱炎性小体对铜绿假单胞菌的反应并降低感染的致病性。特别地，我们研究了小分子ZLN005，它可以转录激活过氧化物酶体增殖体激活受体-γ共激活因子-1α (PGC-1α)，这是线粒体生物发生、抗氧化防御和细胞呼吸的主要调节因子。我们在体外肺上皮细胞和急性肺炎模型中证明，铜绿假单胞菌感染可促进炎性小体成分的表达，并减弱线粒体修复途径的几种成分。ZLN005激活PGC-1α及其下游效应物Sirtuin 3 (SIRT3)， Sirtuin 3是线粒体定位的去乙酰化酶，对细胞代谢过程和活性氧稳态很重要。ZLN005还能减弱P. aeruginosa在支气管上皮细胞中诱导的炎性小体信号，这种作用依赖于ZLN005对SIRT3的激活。在体内肺炎模型中，ZLN005治疗可减少铜绿假单胞菌引起的上皮屏障功能障碍并降低致病性。激活PGC-1α-SIRT3轴的疗法可能为铜绿假单胞菌感染的治疗提供一种补充方法。
The innate immune response to P. aeruginosa pulmonary infections relies on a network of pattern recognition receptors, including intracellular inflammasome complexes, which can recognize both pathogen- and host-derived signals and subsequently promote downstream inflammatory signaling. Current evidence suggests that the inflammasome does not contribute to bacterial clearance and, in fact, that dysregulated inflammasome activation is harmful in acute and chronic P. aeruginosa lung infection. Given the role of mitochondrial damage signals in recruiting inflammasome signaling, we investigated whether mitochondrial-targeted therapies could attenuate inflammasome signaling in response to P. aeruginosa and decrease pathogenicity of infection. In particular, we investigated the small molecule, ZLN005, which transcriptionally activates peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, antioxidant defense, and cellular respiration. We demonstrate that P. aeruginosa infection promotes the expression of inflammasome components and attenuates several components of mitochondrial repair pathways in vitro in lung epithelial cells and in vivo in an acute pneumonia model. ZLN005 activates PGC-1α and its downstream effector, Sirtuin 3 (SIRT3), a mitochondrial-localized deacetylase important for cellular metabolic processes and for reactive oxygen species homeostasis. ZLN005 also attenuates inflammasome signaling induced by P. aeruginosa in bronchial epithelial cells and this action is dependent on ZLN005 activation of SIRT3. ZLN005 treatment reduces epithelial-barrier dysfunction caused by P. aeruginosa and decreases pathogenicity in an in vivo pneumonia model. Therapies that activate the PGC-1α—SIRT3 axis may provide a complementary approach in the treatment of P. aeruginosa infection.
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影响因子：
13.3
作者：
Jabir MS;Hopkins L;Ritchie ND;Ullah I;Bayes HK;Li D;Tourlomousis P;Lupton A;Puleston D;Simon AK;Bryant C;Evans TJ
通讯作者：
Evans TJ
Sirtuin3 对氧化应激和 NLRP3 炎症小体在 ox-LDL 刺激下胆固醇积累和巨噬细胞泡沫细胞形成中的保护作用
影响因子：
5.8
作者：
Ding, Yue;Gong, Weiwei;Meng, Guoliang
通讯作者：
Meng, Guoliang
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
30.5
作者：
Hajjar, AM;Ernst, RK;Miller, SI
通讯作者：
Miller, SI
DOI：
10.4049/jimmunol.1200195
发表时间：
2012-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cai S;Batra S;Wakamatsu N;Pacher P;Jeyaseelan S
通讯作者：
Jeyaseelan S