Cadwell, K, Liu, JY, Brown, SL, Miyoshi, H, Loh, J, Lennerz, JK et al.. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456: 259-263

Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Nature (Impact Factor: 41.46). 11/2008; 456(7219):259-63. DOI: 10.1038/nature07416
Source: PubMed


Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn's disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn's disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn's disease patients carrying the Crohn's disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn's disease patients homozygous for the ATG16L1 Crohn's disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn's disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.

Download full-text


Available from: Barry Sleckman, Dec 29, 2013
  • Source
    • "Autophagy plays important roles in the immune responses and abnormalities in this pathway have been linked to several diseases (Levine et al., 2011). More recently, autophagy has been implicated in regulating secretion (Cadwell et al., 2008; Patel et al., 2013; Ushio et al., 2011; Bhattacharya et al., 2014b), though the underlying mechanisms and in vivo relevance are not fully understood. The role of autophagy in neutrophil functions remains largely unexplored. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy, an intracellular degradation and energy recycling mechanism, is emerging as an important regulator of immune responses. However, the role of autophagy in regulating neutrophil functions is not known. We investigated neutrophil biology using myeloid-specific autophagy-deficient mice and found that autophagy deficiency reduced neutrophil degranulation in vitro and in vivo. Mice with autophagy deficiency showed reduced severity of several neutrophil-mediated inflammatory and autoimmune disease models, including PMA-induced ear inflammation, LPS-induced breakdown of blood-brain barrier, and experimental autoimmune encephalomyelitis. NADPH oxidase-mediated reactive oxygen species generation was also reduced in autophagy-deficient neutrophils, and inhibition of NADPH oxidase reduced neutrophil degranulation, suggesting NADPH oxidase to be a player at the intersection of autophagy and degranulation. Overall, this study establishes autophagy as an important regulator of neutrophil functions and neutrophil-mediated inflammation in vivo.
    Cell Reports 09/2015; 12(11). DOI:10.1016/j.celrep.2015.08.019 · 8.36 Impact Factor
    • "A subset of patients has been described with polymorphism in ATG16L1 (Hampe et al. 2007). ATG16L1 is involved in autophagy, and ATG16L1 deficiency has been associated with deficient Paneth cell function (Cadwell et al. 2008). Polymorphisms in ATG16L1 might therefore affect the capacity of innate immune cells to execute the autophagy pathway and to properly handle intracellular bacteria. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The intestinal microbiota has important metabolic and host-protective functions. Conversely to these beneficial functions, the intestinal microbiota is thought to play a central role in the etiopathogenesis of inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), a chronic inflammation of the gut mucosa. Genetic screens and studies in experimental mouse models have clearly demonstrated that IBD can develop due to excessive translocation of bacteria into the bowel wall or dysregulated handling of bacteria in genetically susceptible hosts. In healthy individuals, the microbiota is efficiently separated from the mucosal immune system of the gut by the gut barrier, a single layer of highly specialized epithelial cells, some of which are equipped with innate immune functions to prevent or control access of bacterial antigens to the mucosal immune cells. It is currently unclear whether the composition of the microbial flora or individual bacterial strains or pathogens induces or supports the pathogenesis of IBD. Further research will be necessary to carefully dissect the contribution of individual bacterial species to this disease and to ascertain whether specific modulation of the intestinal microbiome may represent a valuable further option for future therapeutic strategies.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 08/2015; 56(2). DOI:10.1093/ilar/ilv030 · 2.39 Impact Factor
  • Source
    • "Lysozymes are components and markers of the Paneth cell secretory granule. Abnormal Paneth cells show disorganized or diminished granules that exhibit diffuse cytoplasmic lysozyme staining (Cadwell et al. 2008). We specifically noticed the decreased number of normal Paneth cells (Fig. 3A), shown as the number of Paneth cells per crypt (Fig. 3B) in G93A mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Emerging evidence has demonstrated that intestinal homeostasis and the microbiome play essential roles in neurological diseases, such as Parkinson's disease. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Currently, there is no effective treatment. Most patients die within 3–5 years due to respiratory paralysis. Although the death of motor neurons is a hallmark of ALS, other organs may also contribute to the disease progression. We examined the gut of an ALS mouse model, G93A, which expresses mutant superoxide dismutase (SOD1G93A), and discovered a damaged tight junction structure and increased permeability with a significant reduction in the expression levels of tight junction protein ZO-1 and the adherens junction protein E-cadherin. Furthermore, our data demonstrated increased numbers of abnormal Paneth cells in the intestine of G93A mice. Paneth cells are specialized intestinal epithelial cells that can sense microbes and secrete antimicrobial peptides, thus playing key roles in host innate immune responses and shaping the gut microbiome. A decreased level of the antimicrobial peptides defensin 5 alpha was indeed found in the ALS intestine. These changes were associated with a shifted profile of the intestinal microbiome, including reduced levels of Butyrivibrio Fibrisolvens, Escherichia coli, and Fermicus, in G93A mice. The relative abundance of bacteria was shifted in G93A mice compared to wild-type mice. Principal coordinate analysis indicated a difference in fecal microbial communities between ALS and wild-type mice. Taken together, our study suggests a potential novel role of the intestinal epithelium and microbiome in the progression of ALS.
    04/2015; 3(4). DOI:10.14814/phy2.12356
Show more