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

Billmann-Born, S., Lipinski, S., Bock, J., Till, A., Rosenstiel, P. and Schreiber, S. (2011) The complex interplay of NOD-like receptors and the autophagy machinery in the pathophysiology of Crohn disease European Journal of Cell Biology, 90 (6-7). pp. 593-602. DOI 10.1016/j.ejcb.2010.10.015.

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Abstract

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 antiparasitic 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. (C) 2010 Elsevier GmbH. All rights reserved.

Document Type: Article
Keywords: Crohn disease NOD-like receptors Autophagy Inflammation NOD2/CARD15 ATG16L1 Cytoinvasion Xenophagy intestinal epithelial-cells kappa-b activation inflammatory-bowel-disease innate immune receptors muramyl dipeptide paneth cells life-span signaling pathways transcription factor adaptive immunity
Research affiliation: Kiel University
Refereed: Yes
DOI etc.: 10.1016/j.ejcb.2010.10.015
ISSN: 0171-9335
Date Deposited: 01 Nov 2012 04:59
Last Modified: 23 Jan 2013 10:02
URI: http://eprints.uni-kiel.de/id/eprint/16812

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