Interactions Between Autophagy and the Unfolded Protein Response: Implications for Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis, is characterised by chronic inflammation of the gastrointestinal tract. Aetiology involves a combination of genetic and environmental factors resulting in abnormal immune responses to intestinal microbiota. Genetic studies have strongly linked genes involved in autophagy to CD, and genes involved in the unfolded protein response (UPR) to IBD. The UPR is triggered in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER) and autophagy plays a key role to relieve ER-stress and restore homeostasis. This review summarises the known interactions between autophagy and the UPR and discusses the impact of these converging pathways on IBD pathogenesis. With a paucity of effective long-term treatments for IBD, targeting of synergistic pathways may provide novel and more effective therapeutic options

Inflammatory Bowel Disease Drugs: A Focus on Autophagy

Inflammatory bowel disease [IBD] is characterized by chronic inflammation of the gastrointestinal tract. Medications such as corticosteroids, thiopurines, immunomodulators and biologic agents are used to induce and maintain remission; however, response to these drugs is variable and can diminish over time. Defective autophagy has been strongly linked to IBD pathogenesis, with evidence showing that enhancing autophagy may be therapeutically beneficial by regulating inflammation and clearing intestinal pathogens. It is plausible that the therapeutic effects of some IBD drugs are mediated in part through modulation of the autophagy pathway, with studies investigating a wide range of diseases and cell types demonstrating autophagy pathway regulation by these agents.This review will highlight the current evidence, both in vitro and in vivo, for the modulation of autophagy by drugs routinely used in IBD. A clearer understanding of their mechanisms of action will be invaluable to utilize these drugs in a more targeted and personalized manner in this diverse and often complex group of patients

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

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. 10-week-old male mice (n=6/group) received 3.0% DSS in their drinking water for 4 days, followed by a 14-day recovery period. Mice were treated with 10mg/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 (

The inflammatory bowel disease drug azathioprine induces autophagy via mTORC1 and the unfolded protein response sensor PERK

Background Genetic studies have strongly linked autophagy to Crohn's disease (CD) and stimulating autophagy in CD patients may be therapeutically beneficial. The aim of this study was to evaluate the effect of current inflammatory bowel disease (IBD) drugs on autophagy and investigate molecular mechanisms of action and functional outcomes in relation to this cellular process. Methods Autophagy marker LC3 was evaluated by confocal fluorescence microscopy and flow cytometry. Drug mechanism of action was investigated by PCR Array with changes in signaling pathways examined by immunoblot and RT-qPCR. Clearance of adherent-invasive Escherichia coli (AIEC) and levels of pro-inflammatory cytokine tumour necrosis factor alpha (TNFα) were evaluated by gentamicin protection assays and RT-qPCR respectively. LC3 was analysed in peripheral blood mononuclear cells (PBMC) from paediatric patients by flow cytometry. Results Azathioprine induces autophagy via mechanisms involving modulation of mechanistic target of rapamycin (mTORC1) signaling and stimulation of the unfolded protein response (UPR) sensor PERK. Induction of autophagy with azathioprine correlated with the enhanced clearance of AIEC and dampened AIEC-induced increases in TNFα. Azathioprine induced significant increase in autophagosome bound LC3-II in PBMC populations ex vivo, supporting in vitro findings. In patients, the CD-associated ATG16L1 T300A single-nucleotide polymorphism did not attenuate azathioprine induction of autophagy. Conclusions Modulation of autophagy via mTORC1 and the UPR may contribute to the therapeutic Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporatio