Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity

Area of Science:

• Immunology
• Neuroscience
• Microbiology

Background:

• Mucosal immunity maintains gut microflora and prevents infections.
• Immune and epithelial cells are traditionally viewed as key regulators of gut immunity.
• The role of the enteric nervous system (ENS) in mucosal immunity is less understood.

Purpose of the Study:

• To investigate the role of the ENS in mucosal immunity.
• To determine if enteric neurons contribute to antimicrobial protein (AMP) responses.
• To elucidate the mechanisms by which the ENS governs gut barrier defense.

Main Methods:

• Confocal microscopy and single-molecule fluorescence in situ mRNA hybridization (smFISH) to detect IL-18 in intestinal neurons.
• Genetic deletion of IL-18 specifically in enteric neurons, immune cells, or epithelial cells.
• Infection studies with Salmonella typhimurium (S.t.) in genetically modified mice.
• Unbiased RNA sequencing and single-cell sequencing to analyze molecular pathways.

Main Results:

• Intestinal neurons were identified as a source of the cytokine IL-18.
• Mice with IL-18 deleted from enteric neurons (but not other cell types) became susceptible to S.t. infection.
• Enteric neuronal IL-18 was found to be critical for homeostatic AMP production by goblet cells.
• Neuron-derived IL-18 signaling was shown to control tissue-wide intestinal immunity.

Conclusions:

• The ENS plays an essential, non-redundant role in mucosal immunity.
• Enteric neuronal IL-18 is a key regulator of the antimicrobial response and mucosal barrier integrity.
• Targeting neuron-derived IL-18 signaling may offer new strategies for managing invasive bacterial infections.