TLR4-mediated AKT activation is MyD88/TRIF dependent and critical for induction of oxidative phosphorylation and mitochondrial transcription factor A in murine macrophages.
TLR4-mediated AKT activation is MyD88/TRIF dependent and critical for induction of oxidative phosphorylation and mitochondrial transcription factor A in murine macrophages.
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DOI：
10.4049/jimmunol.1102157
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发表时间：
2012-03-15
期刊：
影响因子：
--
通讯作者：
Samavati L
中科院分区：
文献类型：
--
作者：
Bauerfeld CP;Rastogi R;Pirockinaite G;Lee I;Hüttemann M;Monks B;Birnbaum MJ;Franchi L;Nuñez G;Samavati L
线粒体在细胞的存活和死亡中起着关键作用。在诸如败血症等炎症过程中，线粒体的恢复与细胞存活相关。细胞呼吸、线粒体生物发生及功能的恢复需要核基因和线粒体基因编码的转录因子协同表达，包括线粒体转录因子A（T - fam）和细胞色素c氧化酶（COX，复合物IV）。脂多糖（LPS）在哺乳动物中引发强烈的宿主防御反应，伴有明显的炎症反应，但也触发诸如AKT通路等存活通路的激活。AKT/PKB是一种丝氨酸/苏氨酸蛋白激酶，在细胞存活、蛋白质合成以及响应Toll样受体（TLRs）的炎症调控中发挥重要作用。因此，我们研究了LPS介导的AKT激活在培养的小鼠巨噬细胞（B6 - MCL）和骨髓来源巨噬细胞中的线粒体生物能量学及功能方面的作用。我们发现，LPS刺激通过PI3激酶/AKT通路的早期磷酸化，以时间依赖性方式导致T - fam以及COX亚基I和IV的表达增加。PI3K/AKT通路抑制剂可消除LPS介导的T - fam和COX诱导作用。诱导作用的缺失与ATP产生减少、促炎细胞因子（肿瘤坏死因子 - α）增加、一氧化氮产生以及细胞死亡相关。Toll样受体4（TLR4）介导的AKT激活和线粒体生物发生需要衔接蛋白MyD88以及含Toll - IL - 1R衔接蛋白诱导干扰素 - β（TRIF）的激活。重要的是，通过一种遗传学方法，我们表明AKT1异构体在响应TLR4激动剂调节线粒体生物发生中起关键作用。
Mitochondria play a critical role in cell survival and death. Mitochondrial recovery during inflammatory processes such as sepsis is associated with cell survival. Recovery of cellular respiration, mitochondrial biogenesis and function requires coordinated expression of transcription factors encoded by nuclear and mitochondrial genes, including mitochondrial transcription factor A (T-fam) and cytochrome c oxidase (COX, complex IV). LPS elicits strong host defenses in mammals with pronounced inflammatory responses but also triggers activation of survival pathways such as AKT pathway. AKT/PKB is a serine/threonine protein kinase playing an important role in cell survival, protein synthesis, and controlled inflammation in response to TLRs. Hence, we investigated the role of LPS mediated AKT activation in mitochondrial bioenergetics and function in cultured murine macrophages (B6-MCL) and bone marrow derived macrophages. We show that LPS challenge led to increased expression of T-fam and COX subunit I and IV in a time dependent manner through early phosphorylation of the PI3kinase/AKT pathway. PI3K/AKT pathway inhibitors abrogated LPS mediated T-fam and COX induction. Lack of induction was associated with decreased ATP production, increased proinflammatory cytokines (TNF-α), nitric oxide production and cell death. The TLR4 mediated AKT activation and mitochondrial biogenesis required activation of adaptor protein MyD88 and Toll-IL-1R-containing adaptor inducing IFN-β (TRIF). Importantly, using a genetic approach, we show that the AKT1 isoform is pivotal in regulating mitochondrial biogenesis in response to TLR4 agonist.
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