Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis
Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis
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DOI：
10.1038/s41586-019-1579-3
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发表时间：
2019-10-10
期刊：
影响因子：
64.8
通讯作者：
Veiga-Fernandes, Henrique
中科院分区：
文献类型：
--
作者：
Godinho-Silva, Cristina;Domingues, Rita G.;Veiga-Fernandes, Henrique
第3组先天淋巴样细胞（ILC 3）是炎症、感染、微生物群组成和代谢的主要调节因子（1）。已显示ILC 3和神经元细胞在离散的粘膜位置相互作用以引导粘膜防御（2，3）。然而，目前尚不清楚神经免疫回路是否在生物体水平上运作，整合外部环境信号以协调ILC 3反应。在这里，我们表明，光夹带和脑调节昼夜节律电路调节肠道ILC 3，肠道稳态，肠道防御和宿主脂质代谢的小鼠。我们发现，肠道ILC 3显示时钟基因和ILC 3相关转录因子的昼夜表达。昼夜节律调节剂Arntl的ILC 3自主消融导致肠道ILC 3稳态破坏、上皮反应性受损、微生物组失调、对肠道感染的易感性增加和脂质代谢破坏。ILC 3-内在Arntl的丧失塑造了ILC 3的肠道“邮政编码受体”。引人注目的是，光暗周期，摄食节律和微生物线索差异调节ILC 3时钟，光信号是ILC 3的主要夹带线索。因此，手术或遗传诱导的脑节律失调导致昼夜ILC 3振荡中断，微生物组失调和脂质代谢改变。我们的工作揭示了一种昼夜节律电路，它将环境光线索转化为肠道ILC 3，塑造肠道健康，代谢和生物体内平衡。
Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism(1). ILC3s and neuronal cells have been shown to interact at discrete mucosal locations to steer mucosal defence(2,3). Nevertheless, it is unclear whether neuroimmune circuits operate at an organismal level, integrating extrinsic environmental signals to orchestrate ILC3 responses. Here we show that light-entrained and brain-tuned circadian circuits regulate enteric ILC3s, intestinal homeostasis, gut defence and host lipid metabolism in mice. We found that enteric ILC3s display circadian expression of clock genes and ILC3-related transcription factors. ILC3-autonomous ablation of the circadian regulator Arntl led to disrupted gut ILC3 homeostasis, impaired epithelial reactivity, a deregulated microbiome, increased susceptibility to bowel infection and disrupted lipid metabolism. Loss of ILC3-intrinsic Arntl shaped the gut 'postcode receptors' of ILC3s. Strikingly, light-dark cycles, feeding rhythms and microbial cues differentially regulated ILC3 clocks, with light signals being the major entraining cues of ILC3s. Accordingly, surgically or genetically induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, a deregulated microbiome and altered lipid metabolism. Our work reveals a circadian circuitry that translates environmental light cues into enteric ILC3s, shaping intestinal health, metabolism and organismal homeostasis.