Paneth cells as a site of origin for intestinal inflammation.

The recognition of autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn's disease. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction. As Atg16l1(HM) mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis. Unresolved ER stress is a common feature of inflammatory bowel disease epithelium, and several genetic risk factors of Crohn's disease affect Paneth cells. Here we show that impairment in either UPR (Xbp1(ΔIEC)) or autophagy function (Atg16l1(ΔIEC) or Atg7(ΔIEC)) in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn's-disease-like transmural ileitis if both mechanisms are compromised. Xbp1(ΔIEC) mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1α (IRE1α)-regulated NF-κB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-κB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn's disease as a specific disorder of Paneth cells.

The complex interplay of NOD-like receptors and the autophagy machinery in the pathophysiology of Crohn disease.

Several coding variants of NOD2 and ATG16L1 are associated with increased risk of Crohn disease (CD). NOD2, a cytosolic receptor of the innate immune system activates pro-inflammatory signalling cascades upon recognition of bacterial muramyl dipeptide, but seems also to be involved in antiviral and anti-parasitic defence programs. The CD associated variant L1007fsinsC leads to impaired pro-inflammatory signalling and diminished bacterial clearance. ATG16L1 is a protein essential for autophagosome formation at the phagophore assembly site. The CD associated T300A variant is located in the c-terminal WD40 domain, whose function is still unknown. Basal autophagy is not affected by the T300A variant, but antibacterial autophagy (xenophagy) is impaired, a finding that relates ATG16L1 as well as NOD2 to pathogen defence. Notably, combination of disease-associated alleles of ATG16L1 and NOD2/CARD15 leads to synergistically increased susceptibility for CD, indicating a possible crosstalk between NOD2- and ATG16L1-mediated processes in the pathogenesis of CD. This review surveys current research results and discusses the functional models of potential interplay between NLR-pathways and xenophagy. Interaction between pathways is discussed in the context of reactive oxygen species (ROS), membrane co-localisation, antigen processing and implications of disturbed Paneth cell vesicle export. These effects on pathogen response might imbalance the intestinal barrier epithelia towards chronic inflammation and promote development of Crohn disease. Further elucidation of NOD2/ATG16L1 interplay in xenophagy is relevant for understanding the aetiology of chronic intestinal inflammation and host-microbe interaction in general and could lead to principal new insights to xenophagy induction.