Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Böck J, Martinez-Naves E, Glickman JN, Tschurtschenthaler M, Hartwig J, Hosomi S, Flak MB, Cusick JL, Kohno K, Iwawaki T, Billmann-Born S, Raine T, Bharti R, Lucius R, Kweon MN, Marciniak SJ, Choi A, Hagen SJ, Schreiber S, Rosenstiel P, Kaser A, Blumberg RS.

Nature. 2013 Nov 14;503(7475):272-6. doi: 10.1038/nature12599. Epub 2013 Oct 2.

Richard Blumberg, MD

Richard Blumberg, MD, Brigham and Women’s Hospital

Understanding how the ATG16L1 Crohn’s disease (CD) risk variant that causes autophagy defects leads to the development of spontaneous intestinal inflammation remains enigmatic. Stress in the endoplasmic reticulum (ER) is commonly observed in the intestinal epithelium and specialised Paneth cells in patients suffering from Inflammatory Bowel Disease (IBD). This study establishes a compensatory crosstalk between the unfolded protein response and autophagy in Paneth cells. ER stress renders otherwise innocuous genetic autophagy defects – modelled by Atg16l1 deletion specifically in IECs – into spontaneous ileitis that very closely resembles human small intestinal Crohn’s disease. Mechanistically, ER stress engages the central ER stress sensor IRE1α that instigates NF-κB mediated inflammation – a process that is exacerbated when autophagy is deficient. Importantly, unabated ER stress confined to Paneth cells prompted spontaneous inflammation which unequivocally establishes a role for this sensitive cell type as a site of origin of intestinal inflammation. PMID: 24089213