Neutral ceramidase-dependent regulation of macrophage metabolism directs intestinal immune homeostasis and controls enteric infection.
Neutral ceramidase-dependent regulation of macrophage metabolism directs intestinal immune homeostasis and controls enteric infection.
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DOI：
10.1016/j.celrep.2022.110560
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发表时间：
2022-03-29
期刊：
影响因子：
8.8
通讯作者：
Deng, Zhongbin
中科院分区：
文献类型：
--
作者：
Sun, Rui;Gu, Xuemei;Lei, Chao;Chen, Liang;Chu, Shenghui;Xu, Guangzhong;Doll, Mark A.;Tan, Yi;Feng, Wenke;Siskind, Leah;McClain, Craig J.;Deng, Zhongbin
目前尚不清楚饮食和肠道免疫细胞之间复杂的相互作用如何保护肠道免受感染。中性神经酰胺酶 (NcDase) 在消化膳食鞘脂方面发挥着关键作用。我们发现 NcDase 是控制肠道免疫细胞动态的重要因素。缺乏 NcDase 的小鼠肠道内分化簇 (CD) 8αβ+ T 细胞和干扰素 (IFN)-γ+ T 细胞减少，巨噬细胞增加，并且在啮齿类柠檬酸杆菌感染后无法清除细菌。从机制上讲，细胞 NcDase 或细胞外囊泡 (EV) 相关 NcDase 会产生鞘氨醇，从而促进巨噬细胞驱动的 Th1 免疫。 NcDase 的缺失会影响巨噬细胞中鞘氨醇控制的糖酵解代谢，从而调节巨噬细胞的杀菌活性。重要的是，饮食中给予鞘磷脂和 SphK1 的基因缺失或药理抑制可以预防啮齿类梭菌感染。我们的研究结果表明，鞘氨醇可深刻改变巨噬细胞糖酵解代谢，导致肠道巨噬细胞活化和 T 细胞极化，从而防止病原体在肠道定植。孙等人。发现中性神经酰胺酶塑造肠道免疫景观并驱动巨噬细胞代谢功能，从而控制糖酵解依赖性 PP2A 控制的炎症小体激活、IL-1β 产生和巨噬细胞的杀菌活性。这些数据描述了鞘脂代谢物和针对粘膜病原体的肠道营养免疫之间的肠道内在相互作用。
It is not clear how the complex interactions between diet and intestinal immune cells protect the gut from infection. Neutral ceramidase (NcDase) plays a critical role in digesting dietary sphingolipids. We find that NcDase is an essential factor that controls intestinal immune cell dynamics. Mice lacking NcDase have reduced cluster of differentiation (CD) 8αβ+ T cells and interferon (IFN)-γ+ T cells and increased macrophages in the intestine and fail to clear bacteria after Citrobacter rodentium infection. Mechanistically, cellular NcDase or extracellular vesicle (EV)-related NcDase generates sphingosine, which promotes macrophage-driven Th1 immunity. Loss of NcDase influences sphingosine-controlled glycolytic metabolism in macrophages, which regulates the bactericidal activity of macrophages. Importantly, administration of dietary sphingomyelin and genetic deletion or pharmacological inhibition of SphK1 can protect against C. rodentium infection. Our findings demonstrate that sphingosine profoundly alters macrophage glycolytic metabolism, leading to intestinal macrophage activation and T cell polarization, which prevent pathogen colonization of the gut. Sun et al. find that neutral ceramidase sculpts the intestinal immune landscape and drives macrophage metabolic function and, consequently, glycolysis-dependent PP2A-controlled inflammasome activation, IL-1β production, and bactericidal activity of macrophages. These data describe an intestine-intrinsic interplay between sphingolipid metabolites and gut nutritional immunity against a mucosal pathogen.
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影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1002/hep.31321
发表时间：
2021-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Chu S;Sun R;Gu X;Chen L;Liu M;Guo H;Ju S;Vatsalya V;Feng W;McClain CJ;Deng Z
通讯作者：
Deng Z
影响因子：
29
作者：
Divakaruni AS;Hsieh WY;Minarrieta L;Duong TN;Kim KKO;Desousa BR;Andreyev AY;Bowman CE;Caradonna K;Dranka BP;Ferrick DA;Liesa M;Stiles L;Rogers GW;Braas D;Ciaraldi TP;Wolfgang MJ;Sparwasser T;Berod L;Bensinger SJ;Murphy AN
通讯作者：
Murphy AN
影响因子：
3.6
作者：
Duan, Rui-Dong;Cheng, Yajun;Nilsson, Ake
通讯作者：
Nilsson, Ake
DOI：
10.1002/hep.31628
发表时间：
2021-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Gu X;Sun R;Chen L;Chu S;Doll MA;Li X;Feng W;Siskind L;McClain CJ;Deng Z
通讯作者：
Deng Z