TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons
TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons
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DOI：
10.1073/pnas.1219243110
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发表时间：
2013-03-26
影响因子：
11.1
通讯作者：
Suzuki, Ken
中科院分区：
文献类型：
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作者：
Shintani, Yasunori;Kapoor, Amar;Suzuki, Ken
toll样受体（TLRs）是先天免疫的核心参与者。特别是，TLR9通过识别由感染输入或组织损伤释放的DNA来启动炎症反应。然而，炎症对再生能力差的终末分化器官（如心脏和大脑）是有害的，但TLR9在这些非免疫细胞（包括心肌细胞和神经元）中的作用尚不明确。在这里，我们揭示了TLR9在心肌细胞和神经元的能量代谢和细胞保护中的意想不到的作用。TLR9刺激减少能量底物，增加AMP/ATP比率，随后激活AMP活化激酶（AMPK），导致心肌细胞对缺氧的应激耐受性增加，而不诱导典型的炎症反应。心肌细胞和巨噬细胞之间的表达谱分析发现，unc93同源物B1（秀丽隐杆线虫）通过调节TLR9的亚细胞定位，是TLR9不同反应的关键开关。此外，这种替代性TLR9信号也被发现在分化的神经细胞中起作用。这些数据提出了一个有趣的模型，即相同的配体受体可以同时增加心肌细胞和神经元的应激耐受性，而免疫细胞在组织损伤时诱导炎症。
Toll-like receptors (TLRs) are the central players in innate immunity. In particular, TLR9 initiates inflammatory response by recognizing DNA, imported by infection or released from tissue damage. Inflammation is, however, harmful to terminally differentiated organs, such as the heart and brain, with poor regenerative capacity, yet the role of TLR9 in such nonimmune cells, including cardiomyocytes and neurons, is undefined. Here we uncover an unexpected role of TLR9 in energy metabolism and cellular protection in cardiomyocytes and neurons. TLR9 stimulation reduced energy substrates and increased the AMP/ATP ratio, subsequently activating AMP-activated kinase (AMPK), leading to increased stress tolerance against hypoxia in cardiomyocytes without inducing the canonical inflammatory response. Analysis of the expression profiles between cardiomyocytes and macrophages identified that unc93 homolog B1 (C. elegans) was a pivotal switch for the distinct TLR9 responses by regulating subcellular localization of TLR9. Furthermore, this alternative TLR9 signaling was also found to operate in differentiated neuronal cells. These data propose an intriguing model that the same ligand-receptor can concomitantly increase the stress tolerance in cardiomyocytes and neurons, whereas immune cells induce inflammation upon tissue injury.