The role of innate immune-stimulated epithelial apoptosis during gastrointestinal inflammatory diseases

Abstract

The maintenance of mucosal barrier equilibrium in the intestine requires a delicate and dynamic balance between enterocyte loss by apoptosis and the generation of new cells by proliferation from stem cell precursors at the base of the intestinal crypts. When the balance shifts towards either excessive or insufficient apoptosis, a broad range of gastrointestinal diseases can manifest. Recent work from a variety of laboratories has provided evidence in support of a role for receptors of the innate immune system, including Toll-like receptors 2, 4, and 9 as well as the intracellular pathogen recognition receptor NOD2/CARD15, in the initiation of enterocyte apoptosis. The subsequent induction of enterocyte apoptosis in response to the activation of these innate immune receptors plays a key role in the development of various intestinal diseases, including necrotizing enterocolitis, Crohn's disease, ulcerative colitis, and intestinal cancer. This review will detail the regulatory pathways that govern enterocyte apoptosis, and will explore the role of the innate immune system in the induction of enterocyte apoptosis in gastrointestinal disease.

Fig. 1

Regulation of apoptosis in mammalian cells. As described in the text, apoptosis may be initiated by either extrinsic or intrinsic pathways. The molecular constituents of each of these pathways, and their point of conversion at the mitochondrial membrane, are depicted in this schematic

Fig. 2

TLR4-induced enterocyte apoptosis leads to a disruption in the intestinal epithelial barrier, bacterial translocation, and systemic sepsis. As is described in the text, TLR4 activation leads to the induction of enterocyte apoptosis, which allows for translocation of enteric bacteria, activation of the immune system, and the development of systemic sepsis and inflammation. In response to the disruption in the enterocyte barrier, enterocytes migrate from healthy regions surrounding the mucosal defect, which serves to re-seal the site of disruption and to restore barrier integrity

Fig. 3

The interaction between pattern-recognition receptors determines the extent of TLR4-induced enterocyte apoptosis. As is described in the text, TLR4 activation in enterocytes leads to the induction of apoptosis. In parallel, TLR4 activation has been found to play an important role in facilitating the internalization of microbes into enterocytes. These microbes can then activate intracellular pathogen recognition receptors (PRRs) including TLR9 and NOD2/card15 which serve to limit the extent of TLR4 signaling, to reduce the extent of enterocyte apoptosis, and to preserve barrier integrity