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.

Links of Autophagy Dysfunction to Inflammatory Bowel Disease Onset

“…It is essential to the functioning of both the innate and acquired immune system, and it has a major role in the cell survival. Although there are different types of autophagy, the focus of this review is macroautophagy, and it will hereafter be referred to as autophagy [15]. …”

“…LC3-I is cleaved by the protease Atg4 and then conjugated to phosphatidylethanolamine by the ligases Atg3 and Atg7, forming LC3-II. LC3-II is then inserted into the forming autophagosomal membranes through the actions of the Atg16L1 complex to provide docking sites for cargo selection adaptor proteins, such as sequestosome 1 (SQSTM1/p62), neighbor of BRCA1 (NBR1), nuclear dot protein 52kDa (NDP52), and optineurin [15, 22, 23]. The autophagosome then closes and fuses with lysosomes to form autophagolysosomes and degrade the enclosed cargo.…”

“…NOD2 is an intracellular protein, which is involved in recognition bacterial wall components, and activation of an anti-microbial response through multiple but inter-related inflammatory pathways. NOD2 is thought to interact with Atg16L1 to guide it to sites of bacterial entry, and cells expressing CD-associated NOD2 variant proteins are unable to localize autophagosomes to the correct cellular location for bacterial capture [15]. SQSTM1/p62 is an adaptor protein that targets cargo to the forming autophagosome, and disease-associated variants also result in AIEC intracellular survival and viable bacteria within the cytoplasm of epithelial cells [37].…”

“…Therefore, the gut macrophages are programed to preferentially respond with antimicrobial, and not inflammatory, responses within the mucosa [38]. However, in IBD patients the macrophages respond conversely, with an exaggerated inflammatory response to bacteria and ineffective bacterial clearance [15]. In mouse models, deficiencies in proteins involved in the autophagy pathway (i.e.…”

Impact of epigallocatechin-3-gallate (EGCG), a broad-spectrum anti-inflammatory, in controlling intestinal factors contributing to inflammatory bowel disease.

“…These findings likely arise from alterations in the composition of tight junction proteins that precede any manifestation of disease. Changes in the ratio of pore forming claudins, such as claudin 2, claudin 4, and claudin 8 to pore tightening claudins, such as claudin 1, allow for increased ion flux across the epithelial border, resulting in osmotic diarrhea (Zeissig, Bürgel et al 2007, Förster 2008 Defects in autophagy play a role in the pathogenesis of IBD (Tian, Kabi et al 2001). Genome-wide association searches (GWAS) identified ATG16L1 as an important mutation in IBD patients (Fowler, Doecke et al 2008).…”