Vincristine Leads to Colonic Myenteric Neurons Injury via Stimulating M1 Macrophages Polarization

Background: Vincristine is widely used in treatment of various malignant tumors. The clinical application of vincristine is accompanied by peripheral neurotoxicity. The effect of vincristine on enteric neurons and the underlying mechanism are still unclear. MethodsC57BL6/J mice were systematically treated with vincristine for 10 days, and macrophages were depleted using clodronate liposomes. The colonic myenteric plexus neurons were extracted. Macrophages from different parts were extracted in an improved way.ResultsIn the current study, we demonstrated that system treatment of vincristine resulted in colonic myenteric neurons injury, proinflammatory factors increase and total gastrointestinal transport time increase. Vincristine promoted the M1-type macrophages polarization individually or in coordination with LPS and increased proinflammatory factors IL-1β, IL-6, TNF-α via increasing the phosphorylation of ERK1/2 and p38. In addition, these proinflammatory factors led to colonic myenteric neurons apoptosis targeting on SGK1-FOXO3 pathway. Importantly, macrophage depletion alleviated colonic myenteric neurons injury and the increase of proinflammatory factors caused by system treatment of vincristine.ConclusionsSystem treatment of vincristine led to colonic myenteric neurons injury via stimulating M1 macrophages polarization which was alleviated by depletion of macrophages.