UBE2M, an essential neddylation E2 enzyme, has been implicated in the pathogenesis of various diseases, including cancers, viral infections, and obesity. However, whether UBE2M is involved in the pathogenesis of bacterial sepsis remains unclear. In an Escherichia coli (E. coli)-induced sepsis mouse model, increased UBE2M expression in macrophages in liver and lung tissues postinfection was observed. To further clarify the role of UBE2M in macrophages, mice with macrophage-specific deletion of UBE2M (Lysm+Ube2mf/f) were constructed. Compared with control mice, these mice presented decreased levels of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α; reduced sepsis-induced organ damage; and improved survival. Notably, macrophage-specific deletion of UBE2M did not impair E. coli clearance. In vitro experiments also revealed that UBE2M-deficient macrophages produced fewer proinflammatory cytokines after E. coli infection without hindering E. coli clearance. RNA-sequencing analysis revealed that UBE2M deletion in macrophages after LPS stimulation notably suppressed transcriptional activation within the JAK-STAT and Toll-like receptor signaling pathways, which was further confirmed by gene set enrichment analysis. Additionally, Western blotting results confirmed that UBE2M deletion inhibited the activation of the NF-κB, ERK, and JAK-STAT signaling pathways. In conclusion, our findings indicate that specific deletion of UBE2M in macrophages protects against E. coli-induced sepsis by downregulating the excessive inflammatory response, potentially providing a novel strategy against sepsis by targeting UBE2M.

中文翻译：

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抑制巨噬细胞中的neddylation E2 enzyme UBE2M 可防止大肠杆菌诱导的败血症。


UBE2M 是一种必需的 neddylation E2 酶，与癌症、病毒感染和肥胖等各种疾病的发病机制有关。然而，UBE2M 是否参与细菌性脓毒症的发病机制仍不清楚。在大肠杆菌 （E. coli） 诱导的脓毒症小鼠模型中，观察到感染后肝脏和肺组织中巨噬细胞中 UBE2M 的表达增加。为了进一步阐明 UBE2M 在巨噬细胞中的作用，构建了 UBE2M 巨噬细胞特异性缺失 （Lysm+Ube2mf/f） 的小鼠。与对照小鼠相比，这些小鼠的促炎细胞因子水平降低，例如 IL-1β 、 IL-6 和 TNF-α;减少脓毒症引起的器官损伤;和提高生存率。值得注意的是，UBE2M 的巨噬细胞特异性缺失不会损害大肠杆菌的清除。体外实验还表明，UBE2M 缺陷型巨噬细胞在大肠杆菌感染后产生的促炎细胞因子较少，而不会阻碍大肠杆菌清除。RNA 测序分析显示，LPS 刺激后巨噬细胞中 UBE2M 缺失显著抑制了 JAK-STAT 和 Toll 样受体信号通路内的转录激活，基因集富集分析进一步证实了这一点。此外，Western blotting 结果证实 UBE2M 缺失抑制了 NF-κB 、 ERK 和 JAK-STAT 信号通路的激活。总之，我们的研究结果表明，巨噬细胞中 UBE2M 的特异性缺失通过下调过度的炎症反应来预防大肠杆菌诱导的败血症，可能通过靶向 UBE2M 提供一种对抗败血症的新策略。