A circadian clock is essential for homeostasis of group 3 innate lymphoid cells in the gut
Abstract
Group 3 innate lymphoid cells (ILC3) critically orchestrate host-microbe interactions in the healthy mammalian intestine and become substantially impaired in the context of inflammatory bowel disease (IBD). However, the molecular pathways controlling the homeostasis of ILC3 remain incompletely defined. Here, we identify that intestinal ILC3 are highly enriched in expression of genes involved in the circadian clock and exhibit diurnal oscillations of these pathways in response to light cues. Classical ILC3 effector functions also exhibited diurnal oscillations and lineage-specific deletion of BMAL1, a master regulator of the circadian clock, resulted in dramatically reduced ILC3s selectively in the intestine. BMAL1-deficient ILC3 exhibit impaired expression of Nr1d1 and Per3, hyper-activation of RORγt-dependent target genes, and elevated pro-apoptotic pathways. Depletion of the microbiota with antibiotics partially reduced the hyper-activation of BMAL1-deficient ILC3 and restored cellular homeostasis in the intestine. Finally, ILC3 isolated from the inflamed intestine of patients with IBD exhibit substantial alterations in expression of several circadian-related genes. Our results collectively define that circadian regulation is essential for the homeostasis of ILC3 in the presence of a complex intestinal microbiota, and further that this pathway is disrupted in the context of IBD.
Domains
Life Sciences [q-bio]
Origin : Files produced by the author(s)
