The inner walls of the intestines, known as intestinal mucosa, are highly enriched with ILC3s, which play a major role in mucosal defence and maintenance of epithelial integrity, enabling the intestines to remain in a normal healthy state. While ILC3-derived cytokines are crucial for gut protection, uncontrolled activation can disrupt intestinal homeostasis and cause severe gut pathologies, such as inflammatory bowel disease and Crohn’s disease. Therefore, the critical part of this defence mechanism is to coordinate with environmental cues, such as food intake, diurnal cycle and commensal microbes (friendly bacteria) that constantly challenge the immunological balance within the intestine.
In a new news and views article first authored by Dr Gitalee Sarker, co-authored with Dr Chelsea Larabee and Prof Ana Domingos, Domingos Group researchers analyse the latest works (referenced below) that identify mechanisms by which circadian machinery and feeding behaviours regulate the enteric ILC3s function and thereby maintain gut homeostasis.
One key observation made by the team is that the circadian machinery has great impact on intestinal physiology. Circadian clock genes in the gut epithelial cells regulate barrier integrity. However, it was not known whether such a clock exists in ILCs. Both Seillet et al., 2019 and Gondinho-Silva et al., 2019 have shown for the first time that ILC3s have a rhythmic pattern of expression of major clock genes. Conditional deletion of one of the major clock genes in ILC3s can reduce the number of ILC3s and the amplitude of ILC3-derived IL-22 cytokine production, suggesting that ILC3s require intrinsic circadian clock for their activity.
Another important observation is that the rhythmicity of ILC3s can be impacted by external cues. Seillet et al.,2019 identified feeding habits as a major regulator of ILC3 function, such that food enhances local neuronal VIP-VIPR2 signalling which drives oscillatory production of IL-22 that provides protection against gut inflammation following food consumption. On the other hand, Gondinho-Silva et al., 2019 reported that light entrained signals tuned by the brain circadian clock integrate with the ILC3s intrinsic clock to facilitate the migration of ILC3s to the gut to provide mucosal protection.
The findings of Seillet et al. and Gondinho-Silva et al. have not only identified novel molecular mechanisms through which circadian disruption can induce intestinal disorders, but also expanded our insights into the crosstalk between neurons and ILC3s. Consequently, their observations open up new possibilities to target this neuroimmune axis for novel therapeutic strategies.
According to first author Dr Gitalee Sarker, "Similar to the gut, such regulatory mechanisms may also persist in ILCs in other systems. For example, visceral adipose tissue is highly enriched in ILCs which contribute to inflammation in obesity. Future studies could therefore explore whether feeding behaviour orchestrates adipose function via rhythmic pattern of ILCs activation."
Although these studies have shown the crucial role of local and systemic neuronal signalling in the regulation of ILC3s function, researchers have yet to shed light on the complete circuitry connecting these pathways with the intrinsic clock of ILC3s. Dr Sarker suggests "it would be interesting to address whether central VIP signalling has a role in orchestrating the intrinsic clock of ILC3s."
The full review, ILC3s gut rhythm, published in Nature Immunology, can be accessed here.
Papers referenced in this review:
Seillet, Cyril, et al. "The neuropeptide VIP confers anticipatory mucosal immunity by regulating ILC3 activity." Nature Immunology (2019): 1-10.
Godinho-Silva, Cristina, et al. "Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis." Nature 574.7777 (2019): 254-258.