XBP1 Links ER Stress to Intestinal Inflammation and Confers Genetic Risk for Human Inflammatory Bowel Disease

Abstract

Summary Inflammatory bowel disease (IBD) has been attributed to aberrant mucosal immunity to the intestinal microbiota. The transcription factor XBP1, a key component of the endoplasmic reticulum (ER) stress response, is required for development and maintenance of secretory cells and linked to JNK activation. We report that XBP1 deletion in intestinal epithelial cells (IEC) results in spontaneous enteritis and increased susceptibility to induced colitis secondary to both Paneth cell deficiency and overactive responses of the intestinal epithelial cell (IEC) to the IBD-inducers, TNFα and flagellin. An association of XBP1 variants with human IBD was identified and replicated (rs35873774, P-value 1.6×10−5) with novel, private hypomorphic variants identified as susceptibility factors. Hence, intestinal inflammation can originate solely from XBP1 abnormalities in IEC thus linking cell-specific ER stress to the induction of organ-specific inflammation. We report the first mouse model of spontaneous intestinal inflammation arising from alterations in a genetic risk factor for human IBD.

Tissue damage control in disease tolerance

“…The UPR also exerts protective effects against autoimmune neuroinflammation, as illustrated in mice for the expression of the UPR component protein kinase RNA-like ER kinase (PERK) in olygodendrocytes 85 . As referred above, expression of the UPR component XBP1 in intestinal epithelial cells inhibits colitis in mice while hypomorphic variants of the human XBP1 allele are associated with susceptibility to inflammatory bowel disease 58 . It is worth noticing that the salutary effects exerted by the UPR against the pathogenesis of these immune-mediated inflammatory diseases appear to act essentially in parenchyma cells in which protein synthesis is overabundant, as illustrated for -cells, oligodendrocyte an intestinal epithelial cells, which produce high levels of insulin, myelin and mucins, respectively.…”

“…While the expression of heat shock factor 1 (HSF-1) has been associated with some level of host protection against Listeria monocytogenes infection 56 as well as against endotoxic shock 57 in mice, whether this occurs via a mechanism involving tissue damage control and disease tolerance remains to be established. The UPR on the other hand confers tissue damage control in mice; the expression of X-box binding protein 1 (XBP1) by gut epithelial cells is required to sustain epithelial barrier integrity and anti-microbial activity, preventing gut epithelial damage and colitis 58 …”

“…It is likely that the salutary effects exerted by the UPR in gut epithelial cells relate both to protection from damage imposed by host resistance mechanisms 59 and also by pathogens 58 , such triggered by bacterial pore forming toxins that can disrupt the gut epithelium 10,19 .…”

HIV Protease Inhibitors Induce Endoplasmic Reticulum Stress and Disrupt Barrier Integrity in Intestinal Epithelial Cells

“…11,23 Numerous studies have suggested that ER stress signaling pathways are implicated in various diseases, including atherosclerosis, metabolic disease, liver disease, and inflammatory bowel disease. 6,[24][25][26][27] However, whether HIV PI-induced apoptosis is also associated with the activation of the ER stress response in IECs has not been explored. Herein, we describe our investigation of whether HIV PI-induced activation of the ER stress response is involved in the induction of apoptosis and disruption of normal intestinal barrier function both in in vitro cell culture models and in in vivo mice models.…”

Rôle de la cellule épithéliale dans l’homéostasie intestinale et les maladies inflammatoires chroniques de l’intestin

“…Plusieurs travaux chez l'homme rapportent diverses anomalies d'expression et de fonction des PRR au niveau des cellules épithéliales intestinales [30,37]. Ayabe et al [34] ont observé une surexpression sélec-tive du TLR2 par les cellules de Paneth des cryptes intestinales de MC.…”