Role of Myeloid Cell-Specific TLR9 in Mitochondrial DNA-Induced Lung Inflammation in Mice.
Role of Myeloid Cell-Specific TLR9 in Mitochondrial DNA-Induced Lung Inflammation in Mice.
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骨髓细胞特异性TLR9在小鼠线粒体DNA诱导的肺部炎症中的作用
DOI：
10.3390/ijms24020939
复制
发表时间：
2023-01-04
影响因子：
5.6
通讯作者：
Chu, Hong Wei
中科院分区：
文献类型：
--
作者：
Dimasuay, Kris Genelyn;Berg, Bruce;Schaunaman, Niccolette;Chu, Hong Wei
线粒体功能障碍在包括肥胖在内的各种病理状况中很常见。线粒体功能障碍期间线粒体 DNA (mtDNA) 的释放已被证明在驱动白细胞（包括巨噬细胞）的促炎症反应中发挥作用。然而，mtDNA在体内诱导白细胞炎症反应的机制仍不清楚。此外，线粒体DNA在肥胖环境中如何释放尚不清楚。通过使用骨髓细胞（例如巨噬细胞）中 TLR9 缺陷的小鼠模型，我们发现骨髓细胞中的 TLR9 信号传导对于 mtDNA 介导的促炎症反应（例如中性粒细胞流入和趋化因子产生）至关重要。接触棕榈酸（PA）（一种与肥胖相关的主要饱和脂肪酸）会增强肺巨噬细胞释放线粒体DNA。此外，TLR9 有助于 PA 介导的 mtDNA 释放和炎症反应。对 TLR9 充足的肺巨噬细胞中 RNA 测序数据的通路分析揭示了 PA 上调轴突引导分子基因和下调代谢通路基因。然而，在TLR9缺陷的肺巨噬细胞中，PA下调轴突引导分子基因，但上调代谢途径基因。我们的结果表明，mtDNA 利用白细胞中的 TLR9 信号传导来促进 PA 增加的宿主的肺部炎症反应。此外，TLR9 信号传导参与暴露于 PA 的肺巨噬细胞中轴突导向和代谢途径的调节。
Mitochondrial dysfunction is common in various pathological conditions including obesity. Release of mitochondrial DNA (mtDNA) during mitochondrial dysfunction has been shown to play a role in driving the pro-inflammatory response in leukocytes including macrophages. However, the mechanisms by which mtDNA induces leukocyte inflammatory responses in vivo are still unclear. Moreover, how mtDNA is released in an obese setting has not been well understood. By using a mouse model of TLR9 deficiency in myeloid cells (e.g., macrophages), we found that TLR9 signaling in myeloid cells was critical to mtDNA-mediated pro-inflammatory responses such as neutrophil influx and chemokine production. mtDNA release by lung macrophages was enhanced by exposure to palmitic acid (PA), a major saturated fatty acid related to obesity. Moreover, TLR9 contributed to PA-mediated mtDNA release and inflammatory responses. Pathway analysis of RNA-sequencing data in TLR9-sufficient lung macrophages revealed the up-regulation of axon guidance molecule genes and down-regulation of metabolic pathway genes by PA. However, in TLR9-deficient lung macrophages, PA down-regulated axon guidance molecule genes, but up-regulated metabolic pathway genes. Our results suggest that mtDNA utilizes TLR9 signaling in leukocytes to promote lung inflammatory responses in hosts with increased PA. Moreover, TLR9 signaling is involved in the regulation of axon guidance and metabolic pathways in lung macrophages exposed to PA.
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DOI：
10.1016/j.jconrel.2015.06.016
发表时间：
2015-08-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Gaudin A;Lepetre-Mouelhi S;Mougin J;Parrod M;Pieters G;Garcia-Argote S;Loreau O;Goncalves J;Chacun H;Courbebaisse Y;Clayette P;Desmaële D;Rousseau B;Andrieux K;Couvreur P
通讯作者：
Couvreur P
影响因子：
8
作者：
Ogger PP;Byrne AJ
通讯作者：
Byrne AJ
影响因子：
5.1
作者：
Tashiro H;Takahashi K;Sadamatsu H;Kato G;Kurata K;Kimura S;Sueoka-Aragane N
通讯作者：
Sueoka-Aragane N
影响因子：
3.7
作者：
Bueno, Marta;Zank, Daniel;Mora, Ana L.
通讯作者：
Mora, Ana L.
影响因子：
3.2
作者：
Jiang D;Matsuda J;Berman R;Schaefer N;Stevenson C;Gross J;Zhang B;Sanchez A;Li L;Chu HW
通讯作者：
Chu HW