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

Yalan Huang,Hui Ren,Fengjun Wang,Yanhai Feng,Pei Wang,Yu Wang,Xiaochong He

doi:10.3389/fphys.2019.00606

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.

Highlights

The intestinal epithelia form an important barrier between the intestinal mucosa and the luminal environment
We have found that severe burn injury induced the activation of endoplasmic reticulum (ER) stress in intestinal mucosa, which was accompanied by the activation of autophagy (Huang et al, 2018)
To determine the association between ER stress and autophagy in intestinal mucosa, we detected the level of autophagy after the treatment of ER stress inducers (Tm and Tg) or inhibitor (4-PBA) in mice with or without burn injury

Summary

Introduction

The intestinal epithelia form an important barrier between the intestinal mucosa and the luminal environment. It is well known that increased permeability caused by the disruption of the intestinal epithelial TJ barrier is crucial for the development of intestinal inflammation (Arnott et al, 2000; Arrieta et al, 2009; Turner, 2009). Along with other investigators, have found that severe burn injury directly causes the loss of intestinal barrier function and leads to increased intestinal permeability (Deitch, 1990; Earley et al, 2015), both of which contribute to the development of systemic inflammation and multiple organ failure in severe burn injury (Magnotti and Deitch, 2005; Arrieta et al, 2009; Chen et al, 2012; Clark et al, 2017). The importance of burn-induced intestinal barrier disruption is recognized, the mechanisms of intestinal barrier dysfunction after severe burn injury remain poorly understood

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Results

Conclusion