The Role of Autophagy in Crohn’s Disease

Henderson, Paul; Stevens, Craig

doi:10.3390/cells1030492

Cited by 26 publications

(15 citation statements)

References 179 publications

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“…Genome-wide association studies revealed single-nucleotide polymorphisms in the ATG16L1 gene in CD patients (35). ATG16L1 localized the ATG5/12/16L1 protein complex to the isolation membrane, followed by the formation of an autophagosome double-membrane vesicle (10,12). PI3KCIII activity is required for recruitment of the ATG16L1 protein complex (32).…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium

Koay

Rigby

Wright

2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Koay LC, Rigby RJ, Wright KL. Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 307: G140-G148, 2014. First published May 15, 2014; doi:10.1152/ajpgi.00317.2013.-Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associate impaired autophagy, increased activity in the endocannabinoid system, and upregulation of suppressor of cytokine signaling-3 (SOCS3) protein expression during intestinal inflammation. We have investigated whether these three processes are linked. By assessing the impact of the phytocannabinoid cannabidiol (CBD), the synthetic cannabinoid arachidonyl-2=-chloroethylamide (ACEA), and the endocannabinoid N-arachidonoylethanolamine (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated Caco-2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid type 1 receptor-mediated. In contrast, CBD was able to bypass the cannabinoid type 1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking early and late autophagy. In conclusion, the regulatory protein SOCS3 is regulated by autophagy, and cannabinoids play a role in this process, which could be important when therapeutic applications for the cannabinoids in inflammatory conditions are considered.cannabinoid; autophagy; suppressor of cytokine signaling-3 AUTOPHAGY EXHIBITS MANY physiological roles in the cellular process. Regulation and induction of autophagy correspond to an outcome for the cell: survival or death. During nutrient starving or growth factor deprivation, autophagy acts as the catabolic process to maintain homoeostasis in the cellular context. Stress-induced autophagy will recycle cellular content by transferring energy from a nonessential process to a more crucial cellular process (7,27,40). In contrast to the survival function, autophagy is utilized as a defense mechanism to eliminate the invasion of microbial content (18,23,30). In normal colonic cells, autophagy is required for renewal of the colonic epithelium. Autophagy is active at the lower part of the crypt of the colonic gland, where proliferation of stem cell populations is sustained (11). The importance of autophagy regulation in maintaining homeostasis has linked this system to various pathologies (22,45). Studies have revealed polymorphisms of various autophagy-associated genes (ATG16L1 and IRGM) with increased susceptibility to Crohn's disease (CD) (29,33). Intestinal epithelial cells line the entire gastrointestinal (GI) tract, providing a barrier to microbes and, as such, encounter high exposure to inflammatory st...

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Section: Discussionmentioning

confidence: 99%

Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium

Koay

Rigby

Wright

2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Since the first genome-wide association study (GWAS) on macular degeneration in 2005 1 , over 3,000 GWASs have been published, for more than 1,000 traits, reporting on over tens of thousands of significantly associated genetic variants 2 . Results from GWASs have increased our insight into the genetic architectures of investigated traits, and for some traits, GWAS results have led to further insight into disease mechanisms 3,4 , such as autophagy for Crohn’s disease 5 , immunodeficiency for Rheumatoid arthritis 6 and transcriptome regulation through FOXA2 in the pancreatic islet and liver for Type 2 diabetes 7 . The emerging picture after over a decade of GWASs is that the majority of studied traits are highly polygenic and thus influenced by many genetic variants each of small effect 4,8 , with disparate genetic architectures across traits 9 .…”

Section: Main Textmentioning

confidence: 99%

A global overview of pleiotropy and genetic architecture in complex traits

Watanabe

Stringer

Frei

et al. 2018

Preprint

205

287

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2After a decade of genome-wide association studies (GWASs), fundamental questions in 3 human genetics are still unanswered, such as the extent of pleiotropy across the genome, the 4 nature of trait-associated genetic variants and the disparate genetic architecture across human 5 traits. The current availability of hundreds of GWAS results provide the unique opportunity 6 to gain insight into these questions. In this study, we harmonized and systematically analysed 7 4,155 publicly available GWASs. For a subset of well-powered GWAS on 558 unique traits, 8we provide an extensive overview of pleiotropy and genetic architecture. We show that trait 9 associated loci cover more than half of the genome, and 90% of those loci are associated with 10 multiple trait domains. We further show that potential causal genetic variants are enriched in 11 coding and flanking regions, as well as in regulatory elements, and how trait-polygenicity is 12 related to an estimate of the required sample size to detect 90% of causal genetic variants. 13Our results provide novel insights into how genetic variation contributes to trait variation. All 14 GWAS results can be queried and visualized at the GWAS ATLAS resource 15 (http://atlas.ctglab.nl). 16 across a variety of traits and domains in terms of SNP heritability and trait polygenicity (see 42 Fig. 1). 43 44 Catalogue of 4,155 GWAS summary statistics for 2,965 unique traits 45 Extended DataWe collected publicly available full GWAS summary statistics (last update 23 rd October 46 2018; see Methods). This resulted in 3,555 GWAS summary statistics from 294 studies. We 47 additionally performed GWAS on 600 traits available from the UK Biobank release 2 cohort 48 (UKB2; release May 2017) 12 , by selecting non-binary traits with >50,000 European 49 individuals with non-missing phenotypes, and binary traits for which the number of available 50 cases and controls were each >10,000 and total sample size was >50,000 (see Methods, 51 Supplementary Table 1-2). In total, we collected 4,155 52 Supplementary Information 1 andGWASs from 295 unique studies and 2,965 unique traits (see Supplementary Table 3 for a 53 full list of collected GWASs). Traits were manually classified into 27 standard domains 54 based on previous studies 13,14 . The average sample size across curated GWASs was 56,250 55 subjects. The maximum sample size was 898,130 subjects for a Type 2 Diabetes meta-56 analysis 15 . The 4,155 GWAS results are made available in an online database 57 (http://atlas.ctglab.nl). The database provides a variety of information per trait, including 58 SNP-based and gene-based Manhattan plots, gene-set analyses 16 , SNP heritability 59 estimates 17 , genetic correlations, cross GWAS comparisons and phenome-wide plots. 60For the present study, we restricted our analyses to reasonably powered GWASs (i.e. sample 61 size >50,000), to avoid including SNP effect estimates with relatively large standard errors 62 (see Methods). By selecting a GWAS with the largest sample size per trait, it resulted in 558 63...

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“…We hypothesised that the detrimental effects on bone caused by azathioprine may result in the induction of the autophagy pathway, as azathioprine has already been shown to induce this process in peripheral blood mononuclear cells and colorectal cancer cells [22,34]. Autophagy is a homeostatic process in which cells degrade protein aggregates and damaged organelles [35]. Upon the induction of autophagy, LC3-I becomes lipidated and becomes LC3-II before inserting into the autophagosome membrane [36].…”

Section: Discussionmentioning

confidence: 99%

Azathioprine Has a Deleterious Effect on the Bone Health of Mice with DSS-Induced Inflammatory Bowel Disease

Morgan

Hooper

Milne

et al. 2019

IJMS

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Patients with inflammatory bowel disease (IBD) often present poor bone health and are 40% more at risk of bone fracture. Studies have implicated autophagy in IBD pathology and drugs used to treat IBD stimulate autophagy in varying degrees, however, their effect on the skeleton is currently unknown. Here, we have utilised the dextran sulphate sodium (DSS) model of colitis in mice to examine the effects of the thiopurine drug azathioprine on the skeleton. Ten-week-old male mice (n = 6/group) received 3.0% DSS in their drinking water for four days, followed by a 14-day recovery period. Mice were treated with 10 mg/kg/day azathioprine or vehicle control. Histopathological analysis of the colon from DSS mice revealed significant increases in scores for inflammation severity, extent, and crypt damage (p < 0.05). Azathioprine provided partial protection to the colon, as reflected by a lack of significant difference in crypt damage and tissue regeneration with DSS treatment. MicroCT of vehicle-treated DSS mice revealed azathioprine treatment had a significant detrimental effect on the trabecular bone microarchitecture, independent of DSS treatment. Specifically, significant decreases were observed in bone volume/tissue volume (p < 0.01), and trabecular number (p < 0.05), with a concurrent significant increase in trabecular pattern factor (p < 0.01). Immunohistochemical labelling for LC3 revealed azathioprine to induce autophagy in the bone marrow. Together these data suggest that azathioprine treatment may have a deleterious effect on IBD patients who may already be at increased risk of osteoporotic bone fractures and thus will inform on future treatment strategies for patient stratification.

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The Role of Autophagy in Crohn’s Disease

Cited by 26 publications

References 179 publications

Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium

Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium

A global overview of pleiotropy and genetic architecture in complex traits

Azathioprine Has a Deleterious Effect on the Bone Health of Mice with DSS-Induced Inflammatory Bowel Disease

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