Neuro-epithelial circuits promote sensory convergence and intestinal immunity

Area of Science:

• Immunology
• Neuroscience
• Cell Biology

Background:

• Type 2 inflammation at barrier surfaces is vital for immunity, allergic responses, and tissue repair.
• Epithelial cells and neurons sense environmental triggers and modulate immune responses.
• Coordination of sensory inputs from epithelial, neuronal, and immune cells in type 2 inflammation is not fully understood.

Purpose of the Study:

• To investigate the role of TRPV1+ pain-sensing nociceptors in coordinating epithelial and neuronal signals for type 2 inflammation.
• To elucidate the mechanism by which sensory inputs are integrated to initiate and regulate type 2 immune responses.

Main Methods:

• Chemogenetic silencing and chemical ablation of TRPV1+ nociceptors.
• Spatial transcriptomic and single-cell RNA sequencing.
• Analysis of tuft cell populations and immune responses in vivo.

Main Results:

• TRPV1+ nociceptors co-opt epithelial tuft cells to drive type 2 inflammation.
• Abnormalities in TRPV1+ nociceptors reduce tuft cells and impair anti-helminth immunity.
• Activation of TRPV1+ nociceptors enhances tuft cell accumulation and protective immunity.
• Nociceptor activation stimulates epithelial progenitor cell proliferation and differentiation.
• CGRP receptor signaling in epithelial and tuft cells is essential for type 2 immunity.

Conclusions:

• A neuronal-epithelial tuft cell circuit, involving TRPV1+ nociceptors and CGRP signaling, is a critical upstream regulator of type 2 immunity.
• Sensory convergence within this circuit dictates tissue adaptation and immune responses at barrier surfaces.
• This study reveals a novel mechanism for integrating sensory information to orchestrate protective immune responses.