Salmonella enterica serovar Typhimurium (STm) is a causative pathogen for robust inflammatory gastrointestinal disease and can lead to systemic infection. Eicosanoids, bioactive lipid mediators, play a crucial role in modulating both the induction and resolution of inflammatory responses during an infection. A subset of eicosanoids activates PPARs, nuclear receptor/transcription factors that regulate fatty acid metabolism, lipid body formation, and macrophage function. In this study, we determined that mice lacking PPARα exhibited reduced inflammatory hallmarks of STm infection, including lower inflammatory gene expression, cecal inflammation, and bacterial dissemination, along with a significant increase in cecal eicosanoid metabolism compared to wildtype C57BL/6 mice. In macrophages, STm favored M2b-polarized macrophages for intracellular infection, leading to reduced arachidonic acid and ceramide production. Inhibition of fatty acid oxidation via Etomoxir in STm-infected macrophages reduced bacterial burdens and promoted cell death. In Etomoxir-treated wildtype mice, STm infection increased ceramide production, decreased inflammatory gene expression in the cecum, and increased the number of STm-containing M1 macrophages in mesenteric lymph nodes. These findings revealed a novel role for the lipid-immune signaling axis in Salmonella infections, providing significant insights into the lipid-mediated regulation of inflammation during bacterial infections in the gut.

中文翻译：

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PPARα 通过调节免疫代谢和巨噬细胞极化加剧鼠伤寒沙门氏菌感染。


鼠伤寒沙门氏菌血清型 （STm） 是严重炎症性胃肠道疾病的致病病原体，可导致全身感染。类花生酸是生物活性脂质介质，在感染期间调节炎症反应的诱导和消退中起着至关重要的作用。类花生酸的一个子集激活 PPARs，PPARs，即调节脂肪酸代谢、脂质体形成和巨噬细胞功能的核受体/转录因子。在这项研究中，我们确定缺乏 PPARα 的小鼠表现出 STm 感染的炎症特征降低，包括炎症基因表达降低、盲肠炎症和细菌传播，以及与野生型 C57BL/6 小鼠相比盲肠类花生酸代谢显着增加。在巨噬细胞中，STm 有利于 M2b 极化巨噬细胞进行细胞内感染，导致花生四烯酸和神经酰胺的产生减少。在 STm 感染的巨噬细胞中通过 Etomoxir 抑制脂肪酸氧化，减少了细菌负荷并促进了细胞死亡。在 Etomoxir 处理的野生型小鼠中，STm 感染增加了神经酰胺的产生，降低了盲肠中的炎症基因表达，并增加了肠系膜淋巴结中含有 STm 的 M1 巨噬细胞的数量。这些发现揭示了脂质免疫信号轴在沙门氏菌感染中的新作用，为肠道细菌感染期间脂质介导的炎症调节提供了重要的见解。