PKA signaling controls ILC3 homeostasis and IL-23-mediated inflammation in the gut.

Prostaglandin activates PKA in gut ILC3s to increase tissue-protective factors, while IL-23 lowers PKA negative regulators including PRKAR1A, linking stimulus-specific signaling to gut inflammation.

• Why it matters: ILC3s are enriched in healthy gut but depleted in gastrointestinal disorders, yet how distinct cues reprogram their homeostasis and inflammatory behavior is unclear.
• What they did: The team built a single-cell atlas of ILC3 responses to stimuli, then used lineage-specific Prkar1a deletion in mice and IL-23 overproduction to test effects on PRKAR1A, PKA activity, and inflammation.
• The result: Prkar1a loss reduced ILC3s and increased susceptibility to enteric infection in mice; in adults, continuous PRKAR1A restrains PKA to preserve homeostasis, and IL-23 overproduction downregulated PRKAR1A and increased PKA-driven gut inflammation, with PRKAR1A also reduced by IL-23 or in inflammatory bowel disease in healthy human intestine.

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