WIN55212-2 alleviates acute lung injury by inhibiting macrophage glycolysis through the miR-29b-3p/FOXO3/PFKFB3 axis
WIN55212-2 alleviates acute lung injury by inhibiting macrophage glycolysis through the miR-29b-3p/FOXO3/PFKFB3 axis
复制标题
WIN55212-2通过miR-29b-3p/FOXO3/PFKFB3轴抑制巨噬细胞糖酵解减轻急性肺损伤
DOI：
10.1016/j.molimm.2022.06.005
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发表时间：
2022-07-08
影响因子：
3.6
通讯作者：
Guo, Hui
中科院分区：
文献类型：
--
作者：
He, Quan;Yin, Jun;Guo, Hui
背景：急性肺损伤（acute lung injury，ALI）是脓毒症引起的严重器官功能障碍。WIN 55212 -2（WIN）是一种大麻素受体激动剂。大麻素2型受体的激活可以减轻脓毒症肺损伤，因此，评价WIN对脓毒症相关ALI的影响。方法：采用RT-qPCR方法检测脂多糖（LPS）和WIN处理后MH-S细胞中MiR-29 b-3 p、FOXO 3和PFKFB 3水平以及M1和M2巨噬细胞标志物的水平。ChIP和双荧光素酶报告基因测定确定分子相互作用。Western blotting检测糖酵解相关蛋白。还检测了乳酸和ATP。此外，在脓毒症小鼠模型中测试WIN的作用。HE染色观察小鼠肺组织病理学变化。结果：WIN可抑制LPS诱导的肺泡巨噬细胞M1极化和糖酵解。此外，WIN通过上调miR-29 b-3 p抑制FOXO 3。此外，我们证实FOXO 3通过激活PFKFB 3诱导巨噬细胞M1极化和糖酵解。结论：WIN通过miR-29 b-3 p/FOXO 3/PFKFB 3轴抑制巨噬细胞糖酵解，为减轻脓毒症相关ALI提供了新的治疗靶点。
Background: Acute lung injury (ALI) is a severe organ dysfunction caused by sepsis. WIN55212-2 (WIN) is a cannabinoid receptor agonist. Activation of cannabinoid type 2 receptor can alleviate septic lung injury.Therefore, the effects of WIN on sepsis-related ALI were evaluated.Methods: MiR-29b-3p, FOXO3 and PFKFB3 levels, as well as M1 and M2 macrophage markers were assessed by RT-qPCR in MH-S cells after lipopolysaccharide (LPS) and WIN treatment. ChIP and dual luciferase reporter assays determined molecules interactions. Glycolysis-related proteins were evaluated by Western blotting assay. Lactic acid and ATP were also tested. Furthermore, the effect of WIN was tested in sepsis mice model. HE staining evaluated the histopathological changes in mouse lung tissues. The number of inflammatory cells and macrophages, protein concentration and lactic acid content were detected in mouse bronchoalveolar lavage fluid.Results: We found that WIN suppressed M1 polarization and glycolysis in alveolar macrophages induced by LPS. Moreover, WIN inhibited FOXO3 by up-regulating miR-29b-3p. Furthermore, we verified that FOXO3 induced macrophage M1 polarization and glycolysis through activating PFKFB3. In vivo, WIN alleviated ALI in mice with sepsis.Conclusion: Our results reveal that WIN inhibits macrophage glycolysis through the miR-29b-3p/ FOXO3/PFKFB3 axis, suggesting new therapeutic targets to alleviate sepsis-related ALI.