Indeed, increased ER stress is observed in primary epithelial cells and colonic biopsies from patients with IBD.37–39 Crucially, sustained UPR activation triggers apoptosis, including an ER-specific apoptotic response mediated by ER anchored caspase 12.15 21 In keeping with a detrimental impact of persistent UPR engagement, chronic models of intestinal inflammation, including the TRUC model of IBD described in this study, blockade or genetic deletion of IL22 alleviates disease,8–11 consistent with a non-redundant proinflammatory role for IL22. Here, CASP12 is linked to inflammatory bowel disease.