FOXO1 orchestrates the intestinal homeostasis via neuronal signaling in group 3 innate lymphoid cells

The neuro-immune regulation is associated with homeostasis of the intestine. Intestinal group 3 innate lymphoid cells (ILC3s) are tissue-resident lymphocytes whose functions are affected by the intestine niche. However, how a gut neuronal signal coordinates the immune response of ILC3s is largely unknown. Here, we found that cyclic adenosine monophosphate (cAMP) signaling exacerbated the inflammatory response and attenuated the expression level of the transcription factor forkhead box O1 (FOXO1) in ILC3s. Deficiency of FOXO1 drove the hyperactivation of ILC3s and resulted in gut inflammation independently of T cells. Mechanistically, FOXO1 promoted the transcription of neuropeptide receptor VIPR2 and inhibited the transcription of adrenoceptor ADRA2A in ILC3s. FOXO1-related regulation of VIPR2 and ADRA2A signaling balanced the activation of ILC3s under steady condition or during colitis. Moreover, chronic stress elevated cAMP level and downregulated FOXO1 level, exacerbating intestinal inflammation. Our findings reveal that FOXO1 balances the activation of ILC3s via VIP and adrenergic signaling and regulates intestinal homeostasis. Prof. Wang and colleagues reveal that FOXO1 coordinates gut neuronal signal and immune response of ILC3s. FOXO1-related regulation of VIPR2 and ADRA2A signaling pathways balance the activation of ILC3s under steady conditions or during colitis independently of T cells. Chronic stress elevates cAMP level and downregulates FOXO1 level in ILC3s, exacerbating intestinal inflammation.

Automated summary

This study reveals the association between neuro-immune regulation and intestinal homeostasis. FOXO1 coordinates the immune response of ILC3s through VIP and adrenergic signaling pathways, balancing their activation under steady conditions or during colitis independently of T cells. Chronic stress increases cAMP level and downregulates FOXO1 level in ILC3s, exacerbating intestinal inflammation.