Impact of Paneth Cell Autophagy on Inflammatory Bowel Disease

Abstract

Intestinal mucosal barrier, mainly consisting of the mucus layer and epithelium, functions in absorbing nutrition as well as prevention of the invasion of pathogenic microorganisms. Paneth cell, an important component of mucosal barrier, plays a vital role in maintaining the intestinal homeostasis by producing antimicrobial materials and controlling the host-commensal balance. Current evidence shows that the dysfunction of intestinal mucosal barrier, especially Paneth cell, participates in the onset and progression of inflammatory bowel disease (IBD). Autophagy, a cellular stress response, involves various physiological processes, such as secretion of proteins, production of antimicrobial peptides, and degradation of aberrant organelles or proteins. In the recent years, the roles of autophagy in the pathogenesis of IBD have been increasingly studied. Here in this review, we mainly focus on describing the roles of Paneth cell autophagy in IBD as well as several popular autophagy-related genetic variants in Penath cell and the related therapeutic strategies against IBD.

Keywords: Paneth cell; autophagy; endoplasmic reticulum stress; inflammatory bowel disease; unfolded protein response.

Figure 1

Schematic illustration of roles of intestinal epithelial cells (IEC) autophagy in the prevention of inflammatory bowel disease (IBD). Autophagy process in IECs is induced under inflammation- or immune-related challenge by the formation of the double-membrane autophagosomes. The integrity of autophagosomes and lysosomes leads to the formation of the single-membrane autolysosomes, functioning in degrading and recycling misfolded proteins, or dysfunctional organelles, thus contributing to cellular protection. The Class III-PI3K-Beclin-1 signaling pathway, led to the formation of Class III complex (Beclin-1-Atg14-vacuolar protein sorting(VPS)15-VPS34 complex) is the major inductive pathway to autophagy process, while the Class I-PI3K-mammalian target of rapamycin signaling pathway led to the inhibitory effects on autophagy process. The induction of autophagy protects IECs under stress through the degradation of various kinds of the damage-associated molecular pattern molecules and suppression of stress reaction.

Figure 2

Schematic illustration of mechanisms of Paneth cell autophagy related to endoplasmic reticulum stress (ERS) and reactive oxygen species (ROS) in inflammatory bowel disease alleviation. Under the challenge of stresses, the triggering of the self-protected unfolded protein response process leads to the induction of ERS in Paneth cells. The ERS subsequently results in the induction of autophagy through three signaling pathways, including IRE1-JNK/NK-κB/XBP1, pancreatic ER kinase-eIF2d-activated transcription factor 4, and GRP78-activated transcription factor 6-CHOP signaling pathways. The induction of autophagy thus reduces the over-triggering of the ERS. In addition, the mitochondrial dysfunction triggers the accumulation of the reactive oxygen species (ROS) in Paneth cells. The triggering ROS largely induces autophagy process through the p53-TIGAR/damage-regulated autophagy modulator, p62-NF-E2-related factor 2, as well as BINP3 pathways, thus fighting against cellular damage under stresses.