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NKp46+ lamina propria natural killer cells undergo metabolic reprogramming in a mouse experimental colitis model.
Inflammation Research ( IF 6.7 ) Pub Date : 2020-02-10 , DOI: 10.1007/s00011-020-01324-2
Hongjian Zhou 1 , Xingwang Xie 1 , Bin Jiang 1 , Chao Ke 1
Affiliation  

OBJECTIVE Both innate and adaptive immune system play important roles in the onset and progression of inflammatory bowel diseases (IBDs). However, the significance of natural killer (NK) cells for IBDs remains unclear. To understand the biology of colonic lamina propria natural killer (LPNK) cells in IBDs, we characterized LPNK cell metabolism in a murine acute colitis model. METHODS C57BL/6J mice were fed with 3% dextran sulfate sodium to establish the acute colitis model. Colonic LPNK cells were isolated from mice through flow cytometry. The expression of metabolic genes in LPNK cells was analyzed by transcriptome sequencing and quantitative RT-PCR. Glucose uptake, Seahorse assay, and ATP assay were conducted to assess the metabolic status of LPNK cells. Phos-flow assay was performed to evaluate cell signaling pathways in LPNK cells. In vitro stimulation and cytotoxicity assay were conducted to measure the function of LPNK cells. RESULTS In acute colitis, LPNK cells upregulated the expression of genes related to glycolysis and oxidative phosphorylation (oxphos), and enhanced glucose uptake capability. Intracellular ATP production, glycolysis and oxphos in LPNK cells were also promoted in acute colitis. mTORC1 signaling was essential for the metabolic reprogramming in LPNK cells in acute colitis. Although LPNK cells of diseased mice exhibited equivalent cytokine profile to normal LPNK cells upon stimulation with phorbol ester or IL-2, LPNK cells of diseased mice were more cytotoxic to target cells than normal LPNK cells. CONCLUSIONS LPNK cells undergo metabolic reprogramming which might be a response to upcoming microbial infection in acute colitis.

中文翻译:

NKp46 +固有层天然杀伤细胞在小鼠实验性结肠炎模型中进行代谢重编程。

目的先天性免疫系统和适应性免疫系统在炎症性肠病(IBDs)的发生和发展中均起重要作用。然而,对于IBD,自然杀伤(NK)细胞的重要性尚不清楚。为了了解IBD中结肠固有层自然杀伤(LPNK)细胞的生物学特性,我们在小鼠急性结肠炎模型中表征了LPNK细胞的代谢。方法给C57BL / 6J小鼠饲喂3%的葡聚糖硫酸钠,以建立急性结肠炎模型。通过流式细胞术从小鼠分离结肠LPNK细胞。通过转录组测序和定量RT-PCR分析LPNK细胞中代谢基因的表达。进行葡萄糖摄取,海马测定和ATP测定以评估LPNK细胞的代谢状态。进行光流分析以评估LPNK细胞中的细胞信号通路。进行体外刺激和细胞毒性测定以测量LPNK细胞的功能。结果在急性结肠炎中,LPNK细胞上调了糖酵解和氧化磷酸化(oxphos)相关基因的表达,并增强了葡萄糖摄取能力。在急性结肠炎中,LPNK细胞中的细胞内ATP产生,糖酵解和氧磷也得到促进。mTORC1信号对于急性结肠炎中LPNK细胞的代谢重编程至关重要。尽管患病小鼠的LPNK细胞在受到佛波醇酯或IL-2刺激后表现出与正常LPNK细胞相同的细胞因子谱,但患病小鼠的LPNK细胞对靶细胞的毒性要比正常LPNK细胞高。结论LPNK细胞经过代谢重编程,这可能是对急性结肠炎中即将发生的微生物感染的反应。
更新日期:2020-04-21
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