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Review
. 2010 Jul;10(5):486-502.
doi: 10.2174/156652410791608252.

Autophagy and Crohn's disease: at the crossroads of infection, inflammation, immunity, and cancer

P Brest  1 , E A Corcelle, A Cesaro, A Chargui, A Belaïd, D J Klionsky, V Vouret-Craviari, X Hebuterne, P Hofman, B Mograbi
Affiliations
Review

Autophagy and Crohn's disease: at the crossroads of infection, inflammation, immunity, and cancer

P Brest et al. Curr Mol Med. 2010 Jul.

Abstract

Inflammatory bowel diseases (IBD) are common inflammatory disorders of the gastrointestinal tract that include ulcerative colitis (UC) and Crohn's disease (CD). The incidences of IBD are high in North America and Europe, affecting as many as one in 500 people. These diseases are associated with high morbidity and mortality. Colorectal cancer risk is also increased in IBD, correlating with inflammation severity and duration. IBD are now recognized as complex multigenetic disorders involving at least 32 different risk loci. In 2007, two different autophagy-related genes, ATG16L1 (autophagy-related gene 16-like 1) and IRGM (immunity-related GTPase M) were shown to be specifically involved in CD susceptibility by three independent genome-wide association studies. Soon afterwards, more than forty studies confirmed the involvement of ATG16L1 and IRGM variants in CD susceptibility and gave new information on the importance of macroautophagy (hereafter referred to as autophagy) in the control of infection, inflammation, immunity and cancer. In this review, we discuss how such findings have undoubtedly changed our understanding of CD pathogenesis. A unifying autophagy model then emerges that may help in understanding the development of CD from bacterial infection, to inflammation and finally cancer. The Pandora's box is now open, releasing a wave of hope for new therapeutic strategies in treating Crohn's disease.

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Figures

Fig. (1)
Fig. (1). Functions of Autophagy in Innate Immunity
(A) Structures of the Atg16L1 and IRGM proteins. The two autophagy genes ATG16L1 and IRGM are broadly expressed in intestinal epithelium (colon, small bowel) and in hematopoietic cells (thymus, T cells, and macrophages) [14, 15]. Human Atg16L1 is a platform with an N-terminal domain that interacts with the autophagy proteins Atg5 and Atg12, a coiled-coil domain that mediates homodimeric interactions, and seven WD repeats that are believed to interact with an unknown ligand(s). In contrast, IRGM has a unique, truncated guanosine triphosphatase (GTPase) domain. Several splice isoforms of ATG16L1 and IRGM have been identified. At present, nothing is known about the functions of these different isoforms in autophagy and CD susceptibility. (B) Proposed functions of Atg16L1 and IRGM in xenophagy. Autophagy is a vesicular pathway, enabling cells to digest their own cytosol or invasive bacteria. During autophagy, a portion of cytosol is sequestered within a double-membrane vesicle, called an autophagosome. The autophagosome is formed by expansion of a phagophore, the origin of which remains unknown. During the maturation step, the autophagosome acquires an acidic pH and hydrolases by fusing with a lysosome to generate an autolysosome in which the content is degraded. At the molecular level, a family of at least 16 autophagy-related (Atg) proteins is required for autophagosome formation and maturation. Of these, it is proposed that IRGM may protect the host cells against bacteria by (a) driving vesiculation and disruption of the phagosome, releasing the pathogen out of its protective niche into the cytosol (inset), (b) directing the engulfment of bacteria by large double-membrane autophagosomes, and (c) targeting the pathogen for lysosomal degradation by promoting autolysomal maturation. During autophagosome formation, Atg12 is activated by Atg7 and conjugated by Atg10 to Atg5. The Atg5 (•) / Atg12(•) conjugate then associates with Atg16L1 (•) to form a ~800-kDa multimeric complex (referred to as the Atg16L complex). A fraction of the Atg16L complex localizes to the phagophore and mediates binding of the LC3/Atg8 (•)-phosphatidylethanolamine (ζ) conjugate to promote elongation of the phagophore. Upon completion of the autophagosome, the Atg16L complex and most of the LC3 are released from the membrane. Shown here are the steps controlled by IRGM and Atg16L1 (blue arrows), and the consequences of small-interfering RNA (siRNA)-mediated knockdown of ATG16L1 and IRGM on xenophagy. Images reproduced with permission from [61].
Fig. (2)
Fig. (2). Roles of Autophagy in Chronic Inflammation and Cancer Development
(A) Shown here are the phenotypes of ATG16L1 and IRGM transgenic mice on the production of proinflammatory cytokines. (B) Complex Roles of Autophagy in Cancer Development. Shown in green are the oncogenes, tumor suppressors and ATG genes mutated in human colorectal cancers. In the right panel, enhanced expression of key Atg proteins, LC3 and Beclin 1, is observed in early and advanced stages of CRC. Images reproduced with permission from [110].
Fig. (3)
Fig. (3). Proposed Model of How a Dysregulated Autophagy May Play an Essential Role in Crohn’s Disease Pathogenesis
See text for a detailed explanation. Images reproduced with permission from [129].
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