Intestinal Mucosal Mast Cells: Key Modulators of Barrier Function and Homeostasis

Abstract

The gastrointestinal tract harbours the largest population of mast cells in the body; this highly specialised leukocyte cell type is able to adapt its phenotype and function to the microenvironment in which it resides. Mast cells react to external and internal stimuli thanks to the variety of receptors they express, and carry out effector and regulatory tasks by means of the mediators of different natures they produce. Mast cells are fundamental elements of the intestinal barrier as they regulate epithelial function and integrity, modulate both innate and adaptive mucosal immunity, and maintain neuro-immune interactions, which are key to functioning of the gut. Disruption of the intestinal barrier is associated with increased passage of luminal antigens into the mucosa, which further facilitates mucosal mast cell activation, inflammatory responses, and altered mast cell⁻enteric nerve interaction. Despite intensive research showing gut dysfunction to be associated with increased intestinal permeability and mucosal mast cell activation, the specific mechanisms linking mast cell activity with altered intestinal barrier in human disease remain unclear. This review describes the role played by mast cells in control of the intestinal mucosal barrier and their contribution to digestive diseases.

Keywords: intestinal barrier function; mucosal mast cells.

Figure 1

Intestinal mucosal mast cells. Representative micrographs of human mast cells showing different morphology at the ultrastructural level. (A) Resting mast cell with intact cytoplasmic granules and lipid bodies, displaying regular plasma cell membrane. (B) Activated mast cells showing piecemeal degranulation with loss of intra-granular electrodensity (black arrow) and inter-granular or granule-to-cell membrane fusion and typical channels (white arrow) during anaphylactic degranulation. Magnification 12,000×.

Figure 2

Physiological functions of mast cells in the gastrointestinal tract. Mucosal mast cells play an important role in multiple functions necessary for gut homeostasis, including epithelial, endothelial and neurological functions, tissue transformation, host defence, and immunity.

Figure 3

Experimental procedures to evaluate mast cells. (A) Experimental procedures to evaluate mast cell counts, activation and functional studies. Identification and counting of mast cells can be performed by histochemical dyes and specific staining (above left); activation of mast cells can be assessed by quantification of specific molecules, imaging techniques (granule pattern) and gene and/or protein expression analysis of specific mediators or genes (right); functional studies in in vitro experiments (primary or immortalised cells), in vivo models (mice, rats) and ex vivo by means of organ bath experiments for evaluating mast cell-dependent changes in barrier function or muscle contractility. In addition, a correlation study to associate clinical symptoms with biological data can be conducted. (B) Representative images of intestinal mucosal mast cells: tryptase staining with immunohistochemistry (top, 400×) and immunofluorescence (middle, 400×) and mast cell displaying piecemeal degranulation, observed by electron microscopy (botton, 15,000×). ELISA, enzyme-linked immunosorbent assay; WB, western blot.