LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection
LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection
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LL-37 通过 mTOR 信号传导依赖性线粒体保护减轻炎症损伤
DOI：
10.1016/j.biocel.2014.06.015
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发表时间：
2014
影响因子：
4
通讯作者：
Shao Yongping
中科院分区：
文献类型：
--
作者：
Sun Wenyan;Zheng Yan;Lu Zhuoyang;Wang Hui;Feng Zhihui;Wang Juan;Xiao Shengxiang;Liu Feng;Liu Jiankang;Shao Yongping
人阳离子抗菌蛋白LL-37是一种多功能的宿主防御肽，具有广泛的免疫调节活性。先前的研究表明，LL-37具有促炎和抗炎作用。线粒体在LL-37的皮肤炎症效应中的作用尚未得到充分研究。因此，我们的目的是研究LL-37在HaCaT细胞中的免疫调节作用，并阐明与线粒体功能相关的潜在机制。组织微阵列的免疫组化结果显示慢性皮肤炎症中炎性细胞的细胞质LL-37染色较强。利用外源性LL-37刺激和LL-37敲低和过表达，LL-37被证明显著降低由脂多糖（LPS）诱导的炎性细胞因子包括IL-6、IL-8、IL-1α和肿瘤坏死因子-α（TNF-α）的mRNA水平和蛋白分泌。LL-37的抗炎作用取决于其增加线粒体生物合成和维持线粒体稳态的能力。此外，我们观察到LL-37增强LPS诱导的细胞外信号调节激酶（ERK 1/2）和哺乳动物雷帕霉素靶蛋白（mTOR）的磷酸化。mTOR抑制剂雷帕霉素可以中和LL-37对线粒体的保护作用。总之，这些结果表明，高LL-37表达水平与慢性皮肤炎症相关;炎症期间HaCaT细胞中发生线粒体功能障碍; LL-37通过刺激线粒体生物合成和保护线粒体功能来减轻炎症损伤，这取决于mTOR信号传导。这些发现为LL-37靶向线粒体以预防皮肤炎症反应提供了新的见解。
The human cationic antimicrobial protein LL-37 is a multifunctional host defense peptide with a wide range of immunomodulatory activities. Previous work has shown that LL-37 exerts both pro- and anti-inflammatory effects. The role of mitochondria in the skin inflammatory effects of LL-37 has not been well studied. Therefore, our aim was to investigate the immunomodulatory effect of LL-37 in HaCaT cells and to delineate the underlying mechanisms related to mitochondrial function. Immunohistochemistry results from tissue microarrays showed strong cytoplasmic LL-37 staining in inflammatory cells in chronic dermatic inflammation. Using exogenous LL-37 stimulation and LL-37 knockdown and overexpression, LL-37 was demonstrated to dramatically reduce the mRNA levels and protein secretion of inflammatory cytokines including IL-6, IL-8, IL-1α and tumor necrosis factor-α (TNF-α), which are induced by lipopolysaccharides (LPS). The anti-inflammatory effects of LL-37 are dependent upon its ability to increase mitochondrial biogenesis and to maintain mitochondrial homeostasis. Furthermore, we observed that LL-37 enhances the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK1/2) and mammalian target of rapamycin (mTOR). The mTOR inhibitor rapamycin can neutralize the protective effects of LL-37 on mitochondria. In conclusion, these results suggest that high LL-37 expression levels correlate with chronic skin inflammation; mitochondrial dysfunction occurs in HaCaT cells during inflammation; and LL-37 attenuates inflammatory impairment by stimulating mitochondrial biogenesis and protecting mitochondrial function, which are dependent upon mTOR signaling. These findings provide new insights into targeting mitochondria with LL-37 to prevent skin inflammatory reactions.