Vincristine leads to colonic myenteric neurons injury via pro-inflammatory macrophages activation

Vincristine is widely used in treatment of various malignant tumors. The clinical application of vincristine is accompanied by peripheral neurotoxicity which might not be strictly related to the mechanism of anti-tumor action. There are several possible mechanisms but the effect of vincristine on enteric neurons and the underlying mechanism are still unclear. C57BL6/J mice were systematically treated with vincristine for 10 days, and macrophages were depleted using clodronate liposomes. The colonic myenteric plexus neurons were extracted and cultured in vitro. Macrophages from different parts were extracted in an improved way. In the current study, we demonstrated that system treatment of vincristine resulted in colonic myenteric neurons injury, pro-inflammatory macrophages activation and total gastrointestinal transport time increase. Vincristine promoted the pro-inflammatory macrophages activation individually or in coordination with LPS and increased the expression of pro-inflammatory factors IL-1β, IL-6, TNF-α via increasing the phosphorylation of ERK1/2 and p38. In addition, pro-inflammatory macrophages led to colonic myenteric neurons apoptosis targeting on SGK1-FOXO3 pathway. These effects were attenuated by inhibitors of the ERK1/2 and p38-MAPK pathways. Importantly, macrophages depletion alleviated colonic myenteric neurons injury and the delay of gastrointestinal motility caused by system treatment of vincristine. Taken together, system treatment of vincristine led to colonic myenteric neurons injury via pro-inflammatory macrophages activation which was alleviated by depletion of macrophages.