Mucosal immunology: Mismanaged ER stress and inflammation

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A dysregulated response to endoplasmic reticulum (ER) stress caused by depletion of the transcription factor XBP1 can lead to inflammatory bowel disease.

A new study published in Cell shows that a dysregulated response to endoplasmic reticulum (ER) stress can lead to organ-specific inflammation, and that hypomorphic variants of X-box-binding protein 1 (XBP1) are susceptibility factors for inflammatory bowel disease (IBD) in humans.

ER stress arises following the accumulation of misfolded proteins in the ER during protein synthesis. The unfolded-protein response (UPR) that is induced by this stress protects the cells, especially those with high secretory activity, from apoptosis. The transcription factor XBP1, which is activated by the ER transmembrane protein IRE1 (inositol-requiring transmembrane kinase/endonuclease 1), is an important component of the UPR. XBP1 induces the transcription of genes that are involved in the constitutive maintenance of ER function and is required for the development of highly secretory cells. IRE1 has also been shown to activate JUN N-terminal kinase (JNK).

The intestinal epithelium contains several cell types with high secretory activity — for example, Paneth cells, goblet cells and enteroendocrine cells. To determine whether there is a relationship between the UPR and inflammation, the authors generated mice that specifically lacked expression of functional XBP1 in intestinal epithelial cells (IECs). IECs from these conditionally deleted mice exhibited higher levels of ER stress than those from control mice, as indicated by hyperactivation of IRE1 and increased expression of CHOP (C/EBP homologous protein). These mice also developed spontaneous enteritis, which is typical of IBD.

Further analyses showed that the intestines of these XBP1-deficient mice were devoid of Paneth cells and that this was due to the induction of apoptosis. The intestinal expression of defensins and lysozyme (which are antimicrobial factors that are produced by Paneth cells) was greatly reduced in XBP1-deficient mice compared with control mice.

To determine whether the increase in intestinal inflammation in XBP1-deficient mice was due to hypersensitivity of IECs to typical mucosal inflammatory stimuli, the authors stimulated an IEC line in which the expression of XBP1 was silenced with tumour-necrosis factor (TNF) or flagellin. Loss of XBP1 expression resulted in increased JNK phosphorylation and increased expression of CXC-chemokine ligand 1 by the cells. In addition, IECs from XBP1-deficient mice also expressed higher levels of phosphorylated JNK than IECs from control mice.

These results led the authors to propose a model in which the diminished activity of XBP1 in IECs results in an inefficient UPR. This leads to an increase in ER stress, hyperactivation of IRE1 and increased JNK phosphorylation in response to inflammatory stimuli. In addition, the loss of Paneth cells may be due to an increase in CHOP expression, which has been implicated in programmed cell death in response to excessive ER stress. The subsequent reduction in the expression of antimicrobial factors in the intestine could lead to increased bacterial burden, higher expression of TNF and flagellin and further induction of the inflammatory response by IECs, resulting in the development of spontaneous IBD.

Finally, the authors identified XBP1 as a risk factor for human IBD. Examination of biopsies from patients with IBD showed increased ER stress and IRE1 activity in the intestine compared with control patients. In addition, detailed genetic analysis of these patients identified rare hypomorphic variants of XBP1 as susceptibility factors for both Crohn's disease and ulcerative colitis. So, this study has identified a new genetic risk factor (XBP1) for human IBD that links ER stress in IECs with spontaneous intestinal inflammation.

Olive Leavy

References

Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743–756 (2008) | Article | PubMed |
Todd, D. J., Lee, A. H. & Glimcher, L. H. The endoplasmic reticulum stress response in immunity and autoimmunity. Nature Rev. Immunol. 8, 663–674 (2008) | Article | PubMed |