Role of Autophagy‐Related Genes in the Pathology of Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is a complex, multifactorial disease with genetic, microbial and environmental risk factors combining to result in recurrent inflammation of the intestine. Genetic analyses have uncovered a cluster of IBD risk genes, which regulate a cell stress response called autophagy. Functional studies of these autophagy‐related genes highlight contributions of disease‐associated dysregulation to several aspects of IBD pathology, which include alterations in microbiome composition and bacterial responses (xenophagy), antimicrobial peptide production by Paneth cells (crinophagy), enhanced levels of proinflammatory cytokines and enhanced T‐cell subset responses. This suite of autophagy‐gene regulated responses is modulated not only by the cell type or stimulus, but also by environmental context, with the overall balance of responses critical to the maintenance of health or induction of disease. These findings have opened up new avenues for the development of IBD therapeutics and increased understanding of disease mechanisms to facilitate a more personalised approach to the treatment of IBD.

Key Concepts:

  • Susceptibility to IBD disease is associated with genetic variants in a spectrum of autophagy‐related genes.

  • Autophagy is a tightly regulated catabolic degradative pathway implicated in a number of disease‐associated processes.

  • Autophagy‐dependent processes altered in IBD include intracellular bacterial killing by xenophagy, Paneth cell antimicrobial peptide secretion via crinophagy, production of proinflammatory cytokines by macrophages, antigen presentation and endoplasmic reticulum (ER) stress responses in enterocytes.

  • Xenophagy is impaired by IBD‐associated polymorphisms in ATG16L1, IRGM, NOD2, RIP2, PTPN2 and XBP1 resulting in chronic inflammation due to defective clearance of intracellular pathogens.

  • Both impaired and enhanced crinophagy are observed in Paneth cells from IBD patients. Alterations in crinophagy supress secretion of antimicrobial peptides by these cells.

  • Proinflammatory cytokine production by macrophages is enhanced in IBD. This process is regulated by a balance between autophagy and inflammasome responses. Genetic variants in both pathways are associated with increased IBD susceptibility.

  • Defective autophagy in dendritic cells, through gene knockdown or carriage of disease risk alleles in ATG16L1, IRGM or NOD2, alters antigen presentation and enhances T‐cell stimulation.

  • ER stress activates autophagy through stimulation of the unfolded protein response mediated by XBP1. Disease‐associated alleles of XBP1 are implicated in Paneth cell dysfunction and decreased xenophagy.

Keywords: autophagy; xenophagy; crinophagy; inflammatory bowel disease; genetics; Crohn's disease; Paneth cell; inflammasome; ER stress; proinflammatory cytokine; antigen presentation

Figure 1.

The process of autophagy and autophagy‐related genes associated with inflammatory bowel disease. Autophagy is a stepwise process where cellular stressors (such as bacterial infection) are sensed by stress sensor proteins to induce nucleation of an autophagosome via the action of the ULK and PI3K complexes. The forming membrane is elongated through the actions of the Atg12 and LC3 systems. Cargo is tagged with cargo adaptor proteins and targeted to LC3‐II in the autophagosome membrane. The autophagosome matures through fusion with the lysosome and the contents degraded by lysosomal enzymes. The IBD risk genes associated with autophagy are indicated under the step at which they are thought to act.

Figure 2.

Autophagy‐dependent processes linked to IBD pathogenesis. The process, primary cell type affected and IBD risk genes are indicated. Autophagosomes are depicted as double red circles, secretory vesicles as blue circles, proinflammatory cytokines as green circles, inflammasome as yellow stars, MHC II antigen presentation to CD4+ T cells shown in teal and ER stress as yellow lightning bolts. Size of cartoon is meant to indicate the level of activity.

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Tian, Chaorui, Kabi, Amrita, and McDonald, Christine(Sep 2013) Role of Autophagy‐Related Genes in the Pathology of Inflammatory Bowel Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025006]