Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis

• Published in: Nature (London) 2019-10, Vol.574 (7777), p.254-258
• Main Authors: Godinho-Silva, Cristina, Domingues, Rita G., Rendas, Miguel, Raposo, Bruno, Ribeiro, Hélder, da Silva, Joaquim Alves, Vieira, Ana, Costa, Rui M., Barbosa-Morais, Nuno L., Carvalho, Tânia, Veiga-Fernandes, Henrique
• Format: Article
• Language: English
• Subjects: 13; 13/31; 14; 14/19; 38; 38/39; 45; 45/15; 45/91; 59; 59/5; 59/57; 631/250/2504/2506; 631/250/347; 631/378/1385/2640; 64; 64/60; 82; 96; Ablation; Animals; ARNTL Transcription Factors - deficiency; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Biological Clocks - genetics; Biological Clocks - radiation effects; Bone marrow; Brain; Brain - physiology; Brain - radiation effects; Circadian rhythm; Circadian Rhythm - genetics; Circadian Rhythm - immunology; Circadian Rhythm - physiology; Circadian Rhythm - radiation effects; Circadian rhythms; Circuits; Cues; Deregulation; Digestive system; Entrainment; Feeding Behavior - radiation effects; Female; Gastrointestinal Microbiome - radiation effects; Gastrointestinal tract; Gene expression; Genomes; Health aspects; Homeostasis; Homeostasis - radiation effects; Humanities and Social Sciences; Immune response; Immunity, Innate - radiation effects; Infections; Inflammation; Inflammatory bowel disease; Intestine; Intestines - cytology; Intestines - immunology; Intestines - radiation effects; Kinases; Letter; Light; Light effects; Lipid Metabolism; Lipids; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphocytes - radiation effects; Lymphoid cells; Male; Metabolism; Mice; Microbiomes; Microbiota; Microorganisms; Mucosa; multidisciplinary; Neural circuitry; Observations; Oscillations; Photoperiod; Receptors; Regulators; Science; Science (multidisciplinary); Transcription factors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1579-3

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. Circadian circuits, entrained by light and tuned by the brain, regulate intestinal group 3 innate lymphoid cells in mice, along with epithelial reactivity, microbiome composition and lipid metabolism.