Inflammatory bowel disease: dysfunction of autophagy?

Recent genome-wide association studies identified single nucleotide polymorphisms within gene loci, encoding autophagy genes, e.g. the autophagy-related 16-like 1 (ATG16L1) and the immunity-related GTPase family M (IRGM), as an important risk factor for the onset of chronic inflammatory diseases such as Crohn's disease (CD) or rheumatoid arthritis. CD is characterized by a breakdown of the intestinal epithelial barrier function leading to an overwhelming and uncontrolled immune response to bacterial antigens. Autophagy, and therefore ATG16L1 and IRGM, are critically involved in the innate immune response to invading pathogens. Dysfunction of these molecules results in the increased survival of intracellular bacteria, defective antigen presentation and proinflammatory cytokine secretion. Interestingly, autophagy can also be regulated by other CD susceptibility genes, such as nucleotide oligomerization domain 2 or protein tyrosine phosphatase nonreceptor type 2, and the presence of the CD-associated variations within these genes results in comparable effects. ATG16L1 also plays a crucial role in maintaining Paneth cell function and morphology, while IRGM seems to be associated with mitochondrial function and apoptosis. Dysfunction of these molecules, i.e. of autophagy in vivo, is clearly associated with the increased bacterial infection and the onset of colitis. Interestingly, the phenotype of aberrant Paneth cells and dextran sodium sulphate-induced colitis in ATG16L1 hypomorphic mice closely resembles human CD. Taken together, the available data strongly suggest an important role for autophagy in maintaining intestinal homeostasis, and dysfunction of autophagy seems to be a major risk factor for the onset of chronic intestinal inflammation.