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

Cristina Godinho-Silva, Rita G. Domingues, Miguel Rendas, Bruno Raposo, Hélder Ribeiro, Joaquim Alves da Silva, Ana Vieira, Rui M. Costa, Nuno L. Barbosa-Morais, Tânia Carvalho and Henrique Veiga-Fernandes ()
Additional contact information
Cristina Godinho-Silva: Champalimaud Centre for the Unknown
Rita G. Domingues: Champalimaud Centre for the Unknown
Miguel Rendas: Champalimaud Centre for the Unknown
Bruno Raposo: Champalimaud Centre for the Unknown
Hélder Ribeiro: Champalimaud Centre for the Unknown
Joaquim Alves da Silva: Champalimaud Centre for the Unknown
Ana Vieira: Champalimaud Centre for the Unknown
Rui M. Costa: Champalimaud Centre for the Unknown
Nuno L. Barbosa-Morais: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Tânia Carvalho: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Henrique Veiga-Fernandes: Champalimaud Centre for the Unknown

Nature, 2019, vol. 574, issue 7777, 254-258

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1579-3

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