Du Juan, Li Guoli, Hua Mingxi, Han Junyan, Hao Yu, Zeng Hui, Li Ang, Kong Yaxian
Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
Mediators Inflamm. 2020 Jul 25;2020:5437175. doi: 10.1155/2020/5437175. eCollection 2020.
The cecal ligation and perforation (CLP) model is the gold standard for the polymicrobial sepsis. In the CLP mice, the myeloid cells play an important role in septic shock. The phenotypes and the activation state of the macrophage and neutrophil correlate with their metabolism. In the present study, we generated the specific myeloid deletion of PDK1 and mTOR mice, which was the important regulator of metabolic signaling. We found that the deletion of PDK1 in the myeloid cells could aggravate the early septic shock in the CLP mice, as well as the deletion of mTORC1 and mTORC2. Moreover, PDK1 deletion attenuated the inflammation induced by LPS in the late stage on CLP mice, which was exacerbated in mTORC1 and mTORC2 knockout mice. Both PDK1 and mTORC1/2 could not only regulate the cellular metabolism but also play important roles on the myeloid cells in the secondary stimulation of sepsis. The present study will provide a theoretical prospect for the therapy of the septic shock in different stages.
盲肠结扎穿孔（CLP）模型是多微生物败血症的金标准。在CLP小鼠中，髓样细胞在感染性休克中起重要作用。巨噬细胞和中性粒细胞的表型及活化状态与其代谢相关。在本研究中，我们构建了PDK1和mTOR特异性髓样细胞缺失的小鼠，它们是代谢信号的重要调节因子。我们发现，髓样细胞中PDK1的缺失会加重CLP小鼠的早期感染性休克，mTORC1和mTORC2的缺失也是如此。此外，PDK1的缺失减弱了CLP小鼠后期LPS诱导的炎症，而在mTORC1和mTORC2基因敲除小鼠中炎症加剧。PDK1和mTORC1/2不仅可以调节细胞代谢，在败血症二次刺激时对髓样细胞也起重要作用。本研究将为不同阶段感染性休克的治疗提供理论前景。
