Role of Endoplasmic Reticulum Stress-Autophagy Axis in Severe Burn-Induced Intestinal Tight Junction Barrier Dysfunction in Mice

Abstract

Severe burn injury induces intestinal barrier dysfunction; however, the underlying mechanisms remain elusive. Our previous studies have shown that the intestinal epithelial tight junction (TJ) barrier dysfunction is associated with both endoplasmic reticulum (ER) stress and autophagy in severely burned mice, but the precise role of ER stress and autophagy in the burn-induced intestinal TJ barrier dysfunction needs to be determined. In this study, female C57/BL6 mice were assigned randomly to either sham burn or 30% total body surface area (TBSA) full-thickness burn. The effects of ER stress and autophagy on the intestinal epithelial TJ barrier were validated by inducing or inhibiting both ER stress and autophagy in mice treated with sham burn or burn injury. The intestinal permeability, expression, and localization of TJ proteins, ER stress, and autophagy were assessed by physiological, morphological, and biochemical analyses. The results showed that inducing ER stress with tunicamycin or thapsigargin caused the activation of autophagy, the increase of intestinal permeability, as well as the reduction and reorganization of TJ proteins in the sham-burned mice, and aggravated the burn-induced activation of autophagy, increase of intestinal permeability, as well as the reduction and reorganization of TJ proteins. In contrast, inhibiting ER stress with 4-phenylbutyrate alleviated the burn-induced activation of autophagy, increase of intestinal permeability, as well as the reduction and reorganization of TJ proteins. In addition, inducing autophagy with rapamycin resulted in the increase of intestinal permeability, as well as the reduction and reorganization of TJ proteins in the sham-burned mice, and aggravated the burn-induced increase of intestinal permeability as well as the reduction and reorganization of TJ proteins. However, inhibiting autophagy with 3-methyladenine attenuated the burn-induced increase of intestinal permeability, as well as the reduction and reorganization TJ proteins. It is suggested that the ER stress-autophagy axis contributes to the intestinal epithelial TJ barrier dysfunction after severe burn injury.

Antibiotics induced intestinal tight junction barrier dysfunction is associated with microbiota dysbiosis, activated NLRP3 inflammasome and autophagy

“…In this study, we show that antibiotics activate autophagy, as evidenced by decreased P62 expression and increased LC3-II/LC3-I ratio and Atg5 expression. Although autophagy activation has been reported to be closely associated with intestinal barrier dysfunction [16,51,52], the precise role of autophagy activation in regulating barrier function is still controversial. Some studies have demonstrated that autophagy maintained intestinal or endothelial barrier [53,54].…”

Intestinal barrier dysfunction in severe burn injury

“…Moreover, endoplasmic reticulum stress (ERS)-autophagy pathway has recently been demonstrated to be associated with intestinal epithelial TJ barrier dysfunction induced by severe burn injury [35]. Inhibiting ERS or autophagy with specific inhibitor can significantly ameliorate the severe burn-induced intestinal TJ barrier dysfunction [111]. It is implied that blocking ERS-autophagy pathway may be beneficial to restoring intestinal epithelial TJ barrier dysfunction induced by severe burn injury.…”

Fusobacterium nucleatum Activates Endoplasmic Reticulum Stress to Promote Crohn’s Disease Development via the Upregulation of CARD3 Expression

“…Endoplasmic reticulum (ER), as a membrane-bound organelle, plays a crucial role in folding of secreted and membrane proteins (Huang et al, 2019). If the levels of the unfolded and misfolded proteins exceed the processing capacity of the ER, ER stress (ERS) occurs (Li et al, 2019).…”