Department of Surgery, Division of Immunotherapy, University of Louisville, CTRB 311, 505 South Hancock Street, KY 40202, USA; Department of Oncology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, China; Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Cell Rep. 2022 Mar 29;38(13):110560. doi: 10.1016/j.celrep.2022.110560.
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.
目前尚不清楚饮食与肠道免疫细胞之间的复杂相互作用如何保护肠道免受感染。中性神经酰胺酶（NcDase）在消化膳食神经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一个重要因素。缺乏 NcDase 的小鼠肠道中 CD8αβ T 细胞和干扰素（IFN）-γ T 细胞减少，巨噬细胞增加，在感染柠檬酸杆菌后无法清除细菌。从机制上讲，细胞内 NcDase 或细胞外囊泡（EV）相关 NcDase 产生神经酰胺，促进巨噬细胞驱动的 Th1 免疫。NcDase 的缺失会影响巨噬细胞中受神经酰胺调控的糖酵解代谢，从而调节巨噬细胞的杀菌活性。重要的是，饮食神经鞘磷脂的给药以及 SphK1 的基因缺失或药理学抑制都可以预防柠檬酸杆菌感染。我们的研究结果表明，神经酰胺会深刻改变巨噬细胞的糖酵解代谢，导致肠道巨噬细胞激活和 T 细胞极化，从而防止病原体在肠道定殖。
