Artesunate delays the dysfunction of age-related intestinal epithelial barrier by mitigating endoplasmic reticulum stress/unfolded protein response

The impairment of the intestinal epithelial barrier and subsequent bacterial translocation are common in aging individuals, contributory to several local and systematic disorders. However, the underlying mechanism of the age-related degeneration has not been fully understood. In this study, we demonstrated that the intestinal KIT signaling declined and de-activated with aging, parallel with epithelial barrier dysfunction. Endoplasmic retic-ulum stress (ERS)/unfolded protein response (UPR) was obviously increased during aging. The ERS and its downstream IRE1 alpha were highly activated in the aging colonic epithelium. Furthermore, by the use of Tunica-mycin (Tm)-induced ERS mouse and cell models, we uncovered that the activity of the ERS/IRE1 alpha accelerated the protein degradation of KIT via ubiquitin-proteasome pathway. The deficiency of KIT signaling further reduced the transcription of the tight junction protein Claudin-3. Of significance, Artesunate (ART) could be capable of ameliorating the detrimental effect of ERS/IRE1 alpha, indicated by the re-gained KIT and Claudin-3 ex-pressions and the restoration of the intestinal epithelial barrier. In conclusion, our present study provided novel evidence elucidating the ERS/IRE1 alpha-induced loss of KIT and Claudin-3 in the aging colonic epithelium and also shed light on the protective effect of Artesunate on the intestinal epithelial barrier by blocking ERS/IRE1 alpha ac-tivity during aging.