Neuronal-ILC2 interactions regulate pancreatic glucagon and glucose homeostasis.

Summary

The study identifies a fasting-activated neuroimmune circuit in mice whereby catecholaminergic intestinal neurons drive β2-adrenergic receptor–dependent migration/accumulation of ILC2s to the pancreas to support glucagon secretion and gluconeogenesis. This establishes inter-organ neuronal control of immune cells that orchestrates pancreatic endocrine function and systemic glucose homeostasis.

Key Findings

• ILC2-deficient mice exhibit impaired glucagon secretion, defective hepatic gluconeogenesis, and dysregulated glucose homeostasis during fasting.
• Intestinal ILC2s migrate/accumulate in the pancreas in a β2-adrenergic receptor–dependent manner.
• Activation of catecholaminergic intestinal neurons promotes pancreatic ILC2 accumulation.
• Defines an inter-organ neuroimmune route that supports pancreatic endocrine function under energy deficit.

Clinical Implications

Targeting β2-adrenergic/ILC2 pathways or their mediators could modulate glucagon counter-regulation, informing strategies to prevent hypoglycemia or correct hyperglucagonemia in diabetes.

Limitations

• Mouse-centric evidence; the human existence and magnitude of this pathway remain to be established.
• Molecular mediators linking ILC2s to α-cell glucagon secretion are not delineated in the abstract.

Future Directions

Map human correlates of this neuroimmune circuit; identify cytokines/mediators from ILC2s acting on α-cells; test pharmacologic modulation of β2-adrenergic–ILC2 signaling for hypoglycemia prevention.