Neuroepithelial VIP-VIPR1 interactions differentially control enteric type 1 and type 2 immunity

Area of Science:

• Neuroimmunology
• Gastroenterology
• Innate Immunity

Background:

• The nervous and immune systems interact to maintain mucosal barrier integrity.
• The role of enteric neurons in coordinating gut immunity via neuroepithelial interactions is not fully understood.

Purpose of the Study:

• To identify neuroepithelial interactions that regulate intestinal type 1 and type 2 immunity.
• To elucidate the function of vasoactive intestinal peptide receptor 1 (VIPR1) in gut epithelial cells and its interaction with enteric neurons.

Main Methods:

• Chemogenetic modulation of enteric VIPergic neurons.
• Epithelial-specific gene deletion of Vipr1.
• Analysis of immune cell populations and cytokine profiles.
• Assessment of host susceptibility to bacterial and parasitic infections.

Main Results:

• Gut epithelial cells express VIPR1, and its modulation affects epithelial-derived cytokines.
• Epithelial-intrinsic Vipr1 deletion impairs type 1 immunity (reduced alarmins, intraepithelial lymphocytes).
• Epithelial Vipr1 deficiency enhances type 2 immunity (increased alarmins, tuft cells, ILC2s).
• Disruption of neuroepithelial VIP-VIPR1 signaling increases susceptibility to bacterial infection but enhances resistance to parasite infection.

Conclusions:

• Neuroepithelial interactions involving VIP and VIPR1 play a critical role in differentially regulating intestinal type 1 and type 2 immunity.
• This axis represents a novel multi-tissue mechanism for programming gut immune responses.
• Understanding these interactions is crucial for developing therapeutic strategies against enteric infections.