XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease.
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 hypothesized that a stressful environmental milieu in a rapidly proliferating tissue might instigate a proinflammatory response. We report that Xbp1 deletion in intestinal epithelial cells (IECs) results in spontaneous enteritis and increased susceptibility to induced colitis secondary to both Paneth cell dysfunction and an epithelium that is overly reactive to inducers of IBD such as bacterial products (flagellin) and TNFalpha. An association of XBP1 variants with both forms of human IBD (Crohn's disease and ulcerative colitis) was identified and replicated (rs35873774; p value 1.6 x 10(-5)) with novel, private hypomorphic variants identified as susceptibility factors. Hence, intestinal inflammation can originate solely from XBP1 abnormalities in IECs, thus linking cell-specific ER stress to the induction of organ-specific inflammation.
Kaser
Arthur
A
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Lee
Ann-Hwee
AH
Franke
Andre
A
Glickman
Jonathan N
JN
Zeissig
Sebastian
S
Tilg
Herbert
H
Nieuwenhuis
Edward E S
EE
Higgins
Darren E
DE
Schreiber
Stefan
S
Glimcher
Laurie H
LH
Blumberg
Richard S
RS
D000818:Animals; D017209:Apoptosis; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000473:pathology; D008089:Listeria monocytogenes / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D019879:Paneth Cells / Q000166:cytology / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000276:immunology*; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse
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