Neuroimmune Interactions of Enteric Neurons and Mast Cells: Friends or Foes?

Sammanfattning: Psychological distress or physical strain lead to reduced blood flow in the intestine since other organs are prioritised. One aim of this thesis was to investigate how ischemia followed by reperfusion affects the large intestine and the enteric nervous system (ENS). To do so an experimental ischemia/reperfusion (I/R) model was set up using rat large intestine. In order to study how the ENS reacts to various mediators of stress, primary cultures of myenteric neurons from rat small and large intestine were used to study neuronal survival. The intestinal segments exposed to I/R were structurally well preserved, however, local areas containing numerous mast cells were detected in the muscle layers, the serosa and in and around the myenteric ganglia 4-20 weeks post ischemia. Myenteric ganglionic formations within such mast cell rich areas virtually lacked neurons. Myenteric neurons co-cultured with mast cells showed a markedly reduced neuronal survival. The increased neuronal cell death was largely due to mast cell degranulation. Identified mast cell mediators involved were proteinases acting via proteinase activated receptor 2 (PAR2), prostaglandin D2 (PGD2) and interleukin 6 (IL-6). Immunocytochemical examination of rat small and large intestine, revealed frequent co-localization of corticotropin releasing peptide (CRF), known to induce psychological stress reactions in mammals, and vasoactive intestinal peptide (VIP) in enteric neurons. CRF did not affect the survival of myenteric neurons in culture, but was found to counteract the VIP-induced neuroprotective effect. We also showed that the mast cell-induced increase in cell death of cultured myenteric neurons was not executed via CRF signaling pathways. In conclusion: I/R in rat large intestine attracted mast cells to invade the muscle layers and myenteric ganglia. In mast cell-infiltrated areas, ganglionic formations lacked myenteric neurons. Mast cells reduced neuronal survival when cultured together with myenteric neurons from rat small intestine. The mechanisms behind is through PAR2 activation and release of PGD2 and IL-6. Presence of CRF counteracted VIP-induced neuroprotection in cultured myenteric neurons.