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Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism1. ILC3s and neuronal cells have been shown to interact at discrete mucosal locations to steer mucosal defence2,3. 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.
ILC3s have been shown to be part of discrete mucosal neuroimmune cell units2-5, raising the hypothesis that ILC3s may also integrate systemic neuroimmune circuits to regulate tissue integrity and organismic homeostasis. Circadian rhythms rely on local and systemic cues to coordinate mammalian physiology and are genetically encoded by molecular clocks that allow organisms to anticipate and adapt to extrinsic environmental changes6,7. The circadian clock machinery consists of an autoregulatory network of feedback loops primarily driven by the activators ARNTL and CLOCK and the repressors PER1-PER3, CRY1 and CRY2, amongst others6,7.
Analysis of subsets of intestinal ILCs and their bone marrow progenitors revealed that mature ILC3s express high levels of circadian clock genes (Fig. 1a-c, Extended Data Fig. 1a-d). Notably, ILC3s displayed a circadian pattern of PerlVenus expression (Fig. 1b) and transcriptional analysis of ILC3 revealed circadian expression of master clock regulators and ILC3-related transcription factors (Fig. 1c). To test whether ILC3s are regulated in a circadian manner, we investigated whether intestinal ILC3s require intrinsic clock signals. Thus, we interfered with the expression of the master circadian activator Arntl. Arntfi mice...