Neuroimmune and epithelial interactions in intestinal inflammation

Abstract

The gastrointestinal tract contains the most extensive immune system in the body as well as the largest and most diverse collection of nerves outside of the central nervous system. These systems are continuously involved in ongoing physiological activities of the bowel and they play an active role in pathophysiological processes. It is becoming increasingly clear that intestinal inflammation involves a dynamic interplay between at least three different cell systems: immune cells, neurons and mucosal epithelial cells. A wide array of signalling molecules, including cytokines, neurotransmitters and neurotrophic factors mediate the exchange of information between these cells. Neuroimmune-epithelial interactions that take place in the wall of the gut explain many of pathophysiological features of intestinal inflammation.

Introduction

The enteric nervous system (ENS) is an integrative neural network located within the wall of the gastrointestinal tract. The ENS receives extensive projections from both sympathetic and parasympathetic divisions of the autonomic nervous system and, by way of primary afferent fibres, sends information back to peripheral sympathetic ganglia, the brainstem and spinal cord [1]. In addition to housing this complex neural network, the gut contains the largest component of the immune system in the body, whose function is to survey antigens derived from food, bacteria and parasites and protect the body from environmental toxins and irritants. The ENS and the enteric immune system interact with each other, as well as with specialised cells in the epithelium, including enterocytes, goblet cells and enteroendocrine cells, to elaborate an effective, integrated network of defence 2., 3.. In this review we will consider how nerves in the gut contribute to aspects of host defence in intestinal inflammation through neuroimmune–epithelial interactions. A schematic illustration of these interactions is shown in Fig. 1.

Luminal factors trigger immune and/or epithelial responses that activate enteric nerves, which in turn initiate reflex responses such as increased motility, increased epithelial secretion and vasodilatation. The capacity for bi-directional communication between the elements in this model provides a means for selective and specific modulation of these independent systems by each other, for localised homeostatic regulation. Importantly, many of these potential interactions have not yet been investigated, providing fruitful future opportunities in this rapidly advancing field. Because of its pivotal position in regulation of the barrier function of the gut, the ENS also presents an attractive potential target for pharmacological intervention, particularly because inflammation of the gut, food allergies and parasitic and bacterial infections represent major health problems in developed and developing countries throughout the world.

This review focuses on recent illustrative studies in the intestine that have advanced our understanding of the complex interplay between epithelial cells, nerves and the immune system. Neuroimmune–epithelial interactions involve the local neural circuits of the gut as well as other components of the autonomic nervous system. In addition, the neuroendocrine systems of the brain (the hypothalamo-pituitary-adrenal axis) is also involved, especially in the context of stress; however, involvement of the central nervous system in these interactions is beyond the scope of this review and interested readers are referred to recent related literature 4., 5., 6..