当前位置: X-MOL 学术J. Leukoc. Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
FOXO3a acetylation regulates PINK1, mitophagy, inflammasome activation in murine palmitate-conditioned and diabetic macrophages
Journal of Leukocyte Biology ( IF 3.6 ) Pub Date : 2021-07-20 , DOI: 10.1002/jlb.3a0620-348rr
Priya Gupta 1 , Gaurav Sharma 1 , Amit Lahiri 1 , Manoj Kumar Barthwal 1
Affiliation  

Nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 inflammasome and mitophagy play an important role in cytokine release and diabetes progression; however, the role of saturated fatty acid that is induced under such conditions remains little explored. Therefore, the present study evaluates mechanisms regulating mitophagy and inflammasome activation in primary murine diabetic and palmitate-conditioned wild-type (WT) peritoneal macrophages. Peritoneal macrophage, from the diabetic mice and WT mice, challenged with LPS/ATP and palmitate/LPS/ATP, respectively, showed dysfunctional mitochondria as assessed by their membrane potential, mitochondrial reactive oxygen species (mtROS) production, and mitochondrial DNA (mtDNA) release. A defective mitophagy was observed in the diabetic and palmitate-conditioned macrophages stimulated with LPS/ATP as assessed by translocation of PTEN-induced kinase 1 (PINK1)/Parkin or p62 in the mitochondrial fraction. Consequently, increased apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomerization, caspase-1 activation, and IL1β secretion were observed in LPS/ATP stimulated diabetic and palmitate-conditioned macrophages. LPS/ATP induced Forkhead box O3a (FOXO3a) binding to PINK1 promoter and increased PINK1 mRNA expression in WT macrophages. However, PINK1 mRNA and protein expression were significantly decreased in diabetic and palmitate-conditioned macrophages in response to LPS/ATP. Palmitate-induced acetyl CoA promoted FOXO3a acetylation, which prevented LPS/ATP-induced FOXO3a binding to the PINK1 promoter. C646 (P300 inhibitor) and SRT1720 (SIRT1 activator) prevented FOXO3a acetylation and restored FOXO3a binding to the PINK1 promoter, PINK1 mRNA expression, and mitophagy in palmitate-conditioned macrophages treated with LPS/ATP. Also, a significant decrease in the LPS/ATP-induced mtROS production, mtDNA release, ASC oligomerization, caspase-1 activation, and IL-1β release was observed in the palmitate-conditioned macrophages. Similarly, modulation of FOXO3a acetylation also prevented LPS/ATP-induced mtDNA release and inflammasome activation in diabetic macrophages. Therefore, FOXO3a acetylation regulates PINK1-dependent mitophagy and inflammasome activation in the palmitate-conditioned and diabetic macrophages.

中文翻译:

FOXO3a 乙酰化调节 PINK1、线粒体自噬、小鼠棕榈酸酯条件下和糖尿病巨噬细胞中的炎性体活化

核苷酸结合寡聚化结构域、富含亮氨酸的重复结构域和含有 3 个炎性体和线粒体自噬的 pyrin 结构域在细胞因子释放和糖尿病进展中起重要作用;然而,在这种条件下诱导的饱和脂肪酸的作用仍然很少探索。因此,本研究评估了在原发性小鼠糖尿病和棕榈酸酯条件下的野生型 (WT) 腹腔巨噬细胞中调节线粒体自噬和炎症小体活化的机制。来自糖尿病小鼠和 WT 小鼠的腹膜巨噬细胞分别受到 LPS/ATP 和棕榈酸酯/LPS/ATP 的攻击,通过其膜电位、线粒体活性氧 (mtROS) 产生和线粒体 DNA (mtDNA) 评估显示线粒体功能障碍发布。通过 PTEN 诱导的激酶 1 (PINK1)/Parkin 或 p62 在线粒体部分的易位评估,在 LPS/ATP 刺激的糖尿病和棕榈酸条件巨噬细胞中观察到有缺陷的线粒体自噬。因此,在 LPS/ATP 刺激的糖尿病和棕榈酸条件巨噬细胞中观察到含有 caspase 募集结构域 (ASC) 寡聚化、caspase-1 激活和 IL1β 分泌的凋亡相关斑点样蛋白增加。LPS/ATP 诱导 Forkhead box O3a (FOXO3a) 与 PINK1 启动子结合并增加 WT 巨噬细胞中 PINK1 mRNA 的表达。然而,响应于 LPS/ATP,PINK1 mRNA 和蛋白质表达在糖尿病和棕榈酸条件巨噬细胞中显着降低。棕榈酸酯诱导的乙酰辅酶 A 促进 FOXO3a 乙酰化,这阻止了 LPS/ATP 诱导的 FOXO3a 与 PINK1 启动子的结合。C646(P300 抑制剂)和 SRT1720(SIRT1 激活剂)阻止 FOXO3a 乙酰化并恢复 FOXO3a 与 PINK1 启动子的结合、PINK1 mRNA 表达和用 LPS/ATP 处理的棕榈酸酯条件巨噬细胞中的线粒体自噬。此外,在棕榈酸条件巨噬细胞中观察到 LPS/ATP 诱导的 mtROS 产生、mtDNA 释放、ASC 寡聚化、caspase-1 活化和 IL-1β 释放显着降低。同样,FOXO3a 乙酰化的调节也阻止了 LPS/ATP 诱导的糖尿病巨噬细胞中 mtDNA 的释放和炎症小体的激活。因此,FOXO3a 乙酰化调节棕榈酸酯条件下和糖尿病巨噬细胞中 PINK1 依赖性线粒体自噬和炎性体激活。C646(P300 抑制剂)和 SRT1720(SIRT1 激活剂)阻止 FOXO3a 乙酰化并恢复 FOXO3a 与 PINK1 启动子的结合、PINK1 mRNA 表达和用 LPS/ATP 处理的棕榈酸酯条件巨噬细胞中的线粒体自噬。此外,在棕榈酸条件巨噬细胞中观察到 LPS/ATP 诱导的 mtROS 产生、mtDNA 释放、ASC 寡聚化、caspase-1 活化和 IL-1β 释放显着降低。同样,FOXO3a 乙酰化的调节也阻止了 LPS/ATP 诱导的糖尿病巨噬细胞中 mtDNA 的释放和炎症小体的激活。因此,FOXO3a 乙酰化调节棕榈酸酯条件下和糖尿病巨噬细胞中 PINK1 依赖性线粒体自噬和炎性体激活。C646(P300 抑制剂)和 SRT1720(SIRT1 激活剂)阻止 FOXO3a 乙酰化并恢复 FOXO3a 与 PINK1 启动子的结合、PINK1 mRNA 表达和用 LPS/ATP 处理的棕榈酸酯条件巨噬细胞中的线粒体自噬。此外,在棕榈酸条件巨噬细胞中观察到 LPS/ATP 诱导的 mtROS 产生、mtDNA 释放、ASC 寡聚化、caspase-1 活化和 IL-1β 释放显着降低。同样,FOXO3a 乙酰化的调节也阻止了 LPS/ATP 诱导的糖尿病巨噬细胞中 mtDNA 的释放和炎症小体的激活。因此,FOXO3a 乙酰化调节棕榈酸酯条件下和糖尿病巨噬细胞中 PINK1 依赖性线粒体自噬和炎性体激活。和用 LPS/ATP 处理的棕榈酸条件巨噬细胞中的线粒体自噬。此外,在棕榈酸条件巨噬细胞中观察到 LPS/ATP 诱导的 mtROS 产生、mtDNA 释放、ASC 寡聚化、caspase-1 活化和 IL-1β 释放显着降低。同样,FOXO3a 乙酰化的调节也阻止了 LPS/ATP 诱导的糖尿病巨噬细胞中 mtDNA 的释放和炎症小体的激活。因此,FOXO3a 乙酰化调节棕榈酸酯条件下和糖尿病巨噬细胞中 PINK1 依赖性线粒体自噬和炎性体激活。和用 LPS/ATP 处理的棕榈酸条件巨噬细胞中的线粒体自噬。此外,在棕榈酸条件巨噬细胞中观察到 LPS/ATP 诱导的 mtROS 产生、mtDNA 释放、ASC 寡聚化、caspase-1 活化和 IL-1β 释放显着降低。同样,FOXO3a 乙酰化的调节也阻止了 LPS/ATP 诱导的糖尿病巨噬细胞中 mtDNA 的释放和炎症小体的激活。因此,FOXO3a 乙酰化调节棕榈酸酯条件下和糖尿病巨噬细胞中 PINK1 依赖性线粒体自噬和炎性体激活。FOXO3a 乙酰化的调节也阻止了 LPS/ATP 诱导的糖尿病巨噬细胞中的 mtDNA 释放和炎性体激活。因此,FOXO3a 乙酰化调节棕榈酸酯条件下和糖尿病巨噬细胞中 PINK1 依赖性线粒体自噬和炎性体激活。FOXO3a 乙酰化的调节也阻止了 LPS/ATP 诱导的糖尿病巨噬细胞中的 mtDNA 释放和炎性体激活。因此,FOXO3a 乙酰化调节棕榈酸酯条件下和糖尿病巨噬细胞中 PINK1 依赖性线粒体自噬和炎性体激活。
更新日期:2021-07-20
down
wechat
bug