Activation of resident immune cells induces enteric neuronal death

Abstract

Resident immune cells are involved in the pathogenesis of inflammatory bowel diseases (IBDs). Studies have already demonstrated that these cells, mainly mast cells and macrophages, are close to and in communication with neurons of the enteric nervous system (ENS). Enteric neurons organized in ganglions participate in processes such as control of motility, secretory functions, absorption and blood flow. Morphological and functional changes in these neurons can cause intestinal damage, such as changes in intestinal motility and diarrhea, common features of IBD. Uncontrolled or unregulated activation of mast cells can also interfere with intestinal homeostasis and generate tissue dysfunction and promote inflammation in various gastrointestinal diseases. These cells can also act by releasing mediators that activate enteric glial cells (EGC), leading to reactive gliosis. Despite being recognized as essential regulators of neuronal function in the ENS, when activated by injuries and inflammatory processes, these cells can proliferate and undergo broad activation that, in association with other cells of the external muscular layer of the intestine (neutrophils, monocytes, resident macrophages and smooth muscles) produces and releases pro-inflammatory mediators. This pro-inflammatory action also involves the participation of the beta fraction of the calcium-binding protein S100 (S100β), which despite being found in other cells, in the intestine its expression is limited to EGC. The increase in the expression of this protein may be responsible for the death of neurons, through the activation of receptors for advanced glycation end products (RAGE) and consequent activation of the nuclear transcription factor-κB (NFκB). RAGE-type receptors are expressed in several cells, including their presence in macrophages. It is known that interactions between macrophages and the ENS interfere with intestinal motility, serve as a protective mechanism during injuries and infections, but can also contribute to tissue damage and other gastrointestinal disorders. Therefore, our hypothesis suggests that mast cells and macrophages, resident immune cells, are involved in enteric neuronal death, through the activation of EGCs and the release of pro-inflammatory factors.