Cell death and inflammatory bowel diseases: apoptosis, necrosis, and autophagy in the intestinal epithelium

Abstract

Cell death mechanisms have been associated with the development of inflammatory bowel diseases in humans and mice. Recent studies suggested that a complex crosstalk between autophagy/apoptosis, microbe sensing, and enhanced endoplasmic reticulum stress in the epithelium could play a critical role in these diseases. In addition, necroptosis, a relatively novel programmed necrosis-like pathway associated with TNF receptor activation, seems to be also present in the pathogenesis of Crohn's disease and in specific animal models for intestinal inflammation. This review attempts to cover new data related to cell death mechanisms and inflammatory bowel diseases.

Figure 1

The three major pathways of cell death. Cells can be directed to different programmed cell death mechanisms depending on several factors. In the left, the apoptosis pathway is represented with the characteristic cellular shrinkage and formation of the apoptotic bodies without leakage of contents. In the middle, the necrotic pathway shows the cytosol and organelle swelling and rupture of plasma membrane with subsequent leakage of cellular contents. In the right, autophagy is illustrated with the appearance of vacuoles, the autophagosome, and its fusion with the lysosome, which ends in organelle digestion.

Figure 2

Simplified cartoon of the integrated intestinal homeostatic mechanisms showing the interplay between cell death and innate immunity in intestinal inflammation. Abnormal bacterial sensing through NOD-like and TLR in epithelial cells and dendritic cells in addition to Paneth cell dysfunction are greatly interrelated with the unfolded protein and autophagy pathways. The resulting production of chemokines and cytokines and the activation of immune cells in the lamina propria determine further epithelial barrier defects, with additional exposure to diverse intraluminal contents, enhanced by contact with damage-associated molecular patterns (DAMPs), in a self-perpetuating amplification loop. Figure adapted from Nunes et al. [5].