Journal Article

Intestinal mucosal barrier function in health and disease

Turner, Jerrold R.

2009

Overview

Key Points Mucosal barrier function consists of the combined effects of multiple extracellular and cellular processes that may be disrupted globally or in a targeted manner by physiological and pathophysiological stimuli. In the presence of an intact epithelium, mucosal permeability is primarily determined by tight junction barrier function. Intestinal epithelial cells mediate interactions between the mucosal immune system and luminal materials. The mechanisms by which these epithelia regulate and, conversely, are regulated by the immune system are therefore of crucial importance to mucosal homeostasis and disease. In vitro and in vivo studies have indicated that cytokines, including tumour necrosis factor, LIGHT (also known as TNFSF14), interferon-γ, interleukin-13 (IL-13) and IL-17 can modify epithelial barrier function by mechanisms that include new protein synthesis, membrane trafficking, kinase activation, cytoskeletal modulation and epithelial apoptosis. The contributions of these events to acute and chronic barrier regulation are distinct and may complement one another. Increased intestinal permeability is associated with inflammatory bowel disease but can also be present in healthy individuals. Mouse models confirm that intestinal barrier dysregulation alone is insufficient to cause disease, but they also show that enhanced tight junction permeability can accelerate disease onset and increase severity. In addition to activating pro-inflammatory events, intestinal barrier dysfunction initiates immunoregulatory processes. Defects in these processes may be a cause of inflammatory disease. Further investigation of pathways that integrate mucosal barrier function, or dysfunction, and immune regulation will lead to a better understanding of the mechanisms underlying these complex interactions and provide a rational basis for the development of more effective and targeted therapeutic interventions. Mucosal surfaces are lined by epithelial cells that establish a barrier between external environments and the internal milieu. Recent advances have uncovered mechanisms of barrier regulation by immune stimuli and, conversely, how mucosal immunity is regulated by barrier function. Mucosal surfaces are lined by epithelial cells. These cells establish a barrier between sometimes hostile external environments and the internal milieu. However, mucosae are also responsible for nutrient absorption and waste secretion, which require a selectively permeable barrier. These functions place the mucosal epithelium at the centre of interactions between the mucosal immune system and luminal contents, including dietary antigens and microbial products. Recent advances have uncovered mechanisms by which the intestinal mucosal barrier is regulated in response to physiological and immunological stimuli. Here I discuss these discoveries along with evidence that this regulation shapes mucosal immune responses in the gut and, when dysfunctional, may contribute to disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Absorption / Animals / Antigens / Biomedical and Life Sciences / Biomedicine / Cell Membrane Permeability - immunology / Cell Membrane Permeability - physiology / Cytokines - immunology / Cytokines - metabolism / Cytoskeleton - immunology / Cytoskeleton - metabolism / Disease / Epithelial Cells - immunology / Epithelial Cells - metabolism / Epithelium / Gastrointestinal Tract - immunology / Gastrointestinal Tract - metabolism / Health aspects / Homeostasis - immunology / Homeostasis - physiology / Humans / Immune response / Immune system / Immunity, Mucosal - immunology / Immunology / Intestinal Diseases - immunology / Intestinal Diseases - metabolism / Intestinal mucosa / Intestinal Mucosa - cytology / Intestinal Mucosa - immunology / Intestinal Mucosa - metabolism / Membrane Proteins - immunology / Membrane Proteins - metabolism / Microorganisms / Nutrients / Permeability / Physiological aspects / Physiology / review-article / Skin / Small intestine / Tight Junctions - immunology / Tight Junctions - metabolism