Interstitial cells of Cajal, macrophages and mast cells in the gut musculature: morphology, distribution, spatial and possible functional interactions

Abstract

Interstitial cells of Cajal (ICC) are recognized as pacemaker cells for gastrointestinal movement and are suggested to be mediators of neuromuscular transmission. Intestinal motility disturbances are often associated with a reduced number of ICC and/or ultrastructural damage, sometimes associated with immune cells. Macrophages and mast cells in the intestinal muscularis externa of rodents can be found in close spatial contact with ICC. Macrophages are a constant and regularly distributed cell population in the serosa and at the level of Auerbach's plexus (AP). In human colon, ICC are in close contact with macrophages at the level of AP, suggesting functional interaction. It has therefore been proposed that ICC and macrophages interact. Macrophages and mast cells are considered to play important roles in the innate immune defence by producing pro-inflammatory mediators during classical activation, which may in itself result in damage to the tissue. They also take part in alternative activation which is associated with anti-inflammatory mediators, tissue remodelling and homeostasis, cancer, helminth infections and immunophenotype switch. ICC become damaged under various circumstances - surgical resection, possibly post-operative ileus in rodents - where innate activation takes place, and in helminth infections - where alternative activation takes place. During alternative activation the muscularis macrophage can switch phenotype resulting in up-regulation of F4/80 and the mannose receptor. In more chronic conditions such as Crohn's disease and achalasia, ICC and mast cells develop close spatial contacts and piecemeal degranulation is possibly triggered.

Fig 1

Muscularis externa from mouse small intestine. (A)–(B): Conventional mice, (A) Serosal macrophage containing dense bodies (lysosomes) (D), light vesicles (L), coated vesicle (arrow head), doughnut-shaped vesicle (arrow), nucleus (N), bar: 0.5 μm. B. Macrophage at the level of AP, between the longitudinal muscle layer (LM) and the circular muscle layer (CM), is enveloped by ICC processes (ICC), bar: 1 μm. (C)–(D): Germfree mice, (C) Process of a serosal macrophage between the mesothelium (Me) and the longitudinal muscle layer (LM), bar: 0.5 μm. (D) Macrophage between LM and CM, the macrophages in the germfree mice contain mostly dense bodies, bar: 1 μm. (E) Dextran injected mouse (after 4 days), serosal macrophage between the mesothelium and the longitudinal muscle layer, the macrophage contain large dextran-filled vacuoles (V), light vesicles (L), dense bodies (D) and nucleus (N), bar: 1 μm. (F) Day 15 after infection with Trichinella spiralis, a macrophage (Ma), at the level of AP between LM and CM, is enveloped by ICC cytoplasm characterized by the content of mitochondria (m), the cell borders are marked by a large arrow. The macrophage contains phagocytic vesicles (pv) some lysosomes (L) and coated vesicles (small arrow), bar: 1 μm. Reproduced with kind permission from Wiley-Blackwell: (A–C) [5], Springer: (D) and (E) [34] and American Society for Investigative Pathology: (F) [15].

Fig 2

Whole mounts from rat jejunum. Confocal micrographs. (A–C) Double staining with ED2 (red) towards macrophages and KIT (green) towards ICC. (A) Macrophages in serosa. (B) Macrophages at the level of AP and ICC-AP. (C) Macrophages at the level of DMP and ICC-DMP. Arrows: macrophages, arrowheads: ICC. (D–F) ED1 (CD68) stained macrophages display a granular staining pattern and a ramified morphology. (D) In serosa. (E) At the level of AP. (F) At the level of DMP. Bars: 30 μm.