Global profiling of protein lactylation in microglia in experimental high-altitude cerebral edema

作者：Xiufang Jiang, Jiayue Gao, Xuechao Fei, Yanan Geng, Xiangpei Yue, Zibi Shi, Xiang Cheng, Tong Zhao, Ming Fan, Haitao Wu, Ming Zhao, Lingling Zhu · 发表于：Cell Communication and Signaling · 年份：2024 · DOI：10.1186/s12964-024-01748-x · 被引用次数：25 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、High Altitude and Hypoxia、Cancer, Hypoxia, and Metabolism

BACKGROUND: High-altitude cerebral edema (HACE) is considered an end-stage acute mountain sickness (AMS) that typically occurs in people after rapid ascent to 2500 m or more. While hypoxia is a fundamental feature of the pathophysiological mechanism of HACE, emerging evidence suggests that inflammation serves as a key risk factor in the occurrence and development of this disease. However, little is known about the molecular mechanism underlying their crosstalk. METHODS: A mouse HACE model was established by combination treatment with hypobaric hypoxia exposure and lipopolysaccharides (LPS) stimulation. Lactylated-proteomic analysis of microglia was performed to reveal the global profile of protein lactylation. Molecular modeling was applied to evaluate the 3-D modeling structures. A combination of experimental approaches, including western blotting, quantitative real-time reverse transcriptionpolymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA), confocal microscopy and RNA interference, were used to explore the underlying molecular mechanisms. RESULTS: We found that hypoxia exposure increased the lactate concentration and lactylation in mouse HACE model. Moreover, hypoxia aggravated the microglial neuroinflammatory response in a lactate-dependent manner. Global profiling of protein lactylation has shown that a large quantity of lysine-lactylated proteins are induced by hypoxia and preferentially occur in protein complexes, such as the NuRD comple...