A neuro-epithelial unit regulates immunohomeostasis at barrier surfaces

Barrier tissues are sites of constant environmental exposure and require tightly coordinated mechanisms to maintain immune homeostasis while preserving tissue integrity. Emerging evidence supports the concept of a neuro-epithelial unit, in which neurons and epithelial cells function as integrated regulatory modules. In this review, we discuss how epithelial cells and peripheral neurons communicate to sense environmental cues and orchestrate immune responses. Epithelial cells provide a physical and biochemical barrier, while neurons rapidly detect perturbations and modulate local immune and stromal compartments through neuropeptide release. This coordinated interaction shapes immune cell recruitment, activation, and tolerance at barrier surfaces, such as the intestine. Here, we highlight recent advances demonstrating that neuronal signaling directly influences epithelial renewal, barrier function, and inflammatory responses. Furthermore, we explore how dysregulation of this neuro-epithelial axis contributes to chronic inflammatory diseases. Understanding the principles governing neuro-epithelial crosstalk may uncover novel therapeutic strategies to restore tissue homeostasis and treat barrier-associated disorders.