The macrophage system in the intestinal muscularis externa during inflammation: an immunohistochemical and quantitative study of osteopetrotic mice

Abstract

Intestinal inflammation results in disturbed intestinal motility in humans as well as in animal models. This altered function of smooth muscle cells and/or the enteric nervous system may be caused by activation of macrophages in muscularis externa and a thereby following release of cytokines and chemokines that causes influx of mononuclear cells and neutrophilic granulocytes. We subjected osteopetrotic (op/op) mice that lack certain macrophage subtypes, e.g. macrophages in the muscularis externa and +/+ mice to LPS to induce inflammatory cell influx. The densities of F4/80+, MHCII+, and myeloperoxidase+ cells were quantified using stereological sampling. In +/+ mice we found that MHCII+ cells outnumber F4/80+ cells and that LPS injection increased the density of MHCII+ cells temporarily but not that of F4/80+ cells. This indicates that an upregulation of MHCII antigen takes place and that two or more macrophage subtypes with comparable morphologies exist. Osteopetrotic mice lacked MHCII+, CD169+, and F4/80+ cells after either treatment, which indicate that these cells are CSF-1-dependent. LPS induced VCAM-1 activation of the vessels, modest influx of granulocytes, as well as an iNOS-activation in a cell type different from macrophages in both +/+ and op/op mice.

Immune mediators of postoperative ileus

“…Eskandari et al demonstrated that the resident muscularis macrophages express the CD14 molecule that is necessary for LPS signaling after binding to its receptor [18]. LPS challenge led to cellular activation and production of inducible nitric oxide synthase (iNOS) thereby demonstrating that these cells are able to contribute in immunoresponses [19,20]. The immunological competence of these normally quiescent macrophages in POI development has been shown 1 year later in 1998 in a rat model of intestinal manipulation.…”

Neuroimmune mechanisms in postoperative ileus

“…It was hypothessed that intestinal manipulation activates resident macrophages present in the intestinal muscularis externa. These normally quiescent macrophages are organised into a layer or “network” at the level of the myenteric plexus and at the serosal side of the intestine 24 25 26. Activation of these phagocytes subsequently resulted in cytokine and chemokine release, followed by an influx of leucocytes starting approximately 3–4 h after surgery.…”

“…Under healthy conditions, such resident macrophages are organised into a layer at the level of the myenteric plexus (between the longitudinal and circular muscle layer) and in the intestinal serosa 24 25 26. Most of these cells possess phagocytic properties, express LPS-binding receptor CD1439 and are activated by LPS 26 40 41. Moreover, muscularis macrophages stain for macrophage scavenger receptor CD163, which has been shown to possess bacteria binding and sensing capacities 42.…”

Extending the knowledge in histochemistry and cell biology

“…The authors interpreted their Wndings to support an even more important role of lymphotoxin-receptor signaling for the development of metallophilic macrophages, which had been reported previously (Milicevic et al 2006). Mikkelsen et al (2008) put particular emphasis on studying the macrophage system in the intestinal muscularis externa during inXammation. Wildtype and osteopetrotic mice, which lack macrophages in the muscularis externa due to deWciency in colony stimulating factor 1, were challenged with LPS to induce inXammation.…”