Endoplasmic reticulum stress and intestinal inflammation

Abstract

The intestinal epithelial cell (IEC) is increasingly recognized to play a prominent role as an important intermediary between the commensal microbiota and the intestinal immune system. Moreover, it is now recognized that intestinal inflammation in inflammatory bowel disease (IBD) may arise primarily from IEC dysfunction due to unresolved endoplasmic reticulum (ER) stress as a consequence of genetic disruption of X box binding protein-1 function. In addition to primary (genetic) abnormalities of the unfolded protein response, a variety of secondary (inflammation and environmental) factors are also likely to be important regulators of ER stress. ER stress pathways are also well known to regulate (and be regulated by) autophagy pathways. Therefore, the host’s ability to manage ER stress is likely to be a major pathway in the pathogenesis of intestinal inflammation that arises primarily from the IEC. Herein we discuss ER stress in the IEC as both an originator and perpetuator of intestinal inflammation in IBD.

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

“…Both the UPR and inflammation are important protective cellular/tissue responses that when deregulated can lead to cellular damage. In line with this, UPR dysfunction is involved in many autoimmune and inflammatory disorders, such as diabetes (Hotamisligil 2010, Kaser & Blumberg 2010, Oslowski & Urano 2011a, Chaudhari et al 2014.…”

The microbiota in inflammatory bowel disease

“…Protective effect in UC [27] pathway. The unfolded protein pathway genes XBP1 and ORMDL3 have been associated with CD and UC, and are closely linked to autophagy [42]. Autophagy appears to be a key converging pathway for the strongest genetic risk factors for IBD that result in inappropriate innate immune responses to the microbiota.…”

Fexofenadine Regulates Nuclear Factor-κB Signaling and Endoplasmic Reticulum Stress in Intestinal Epithelial Cells and Ameliorates Acute and Chronic Colitis in Mice

“…More importantly, the mechanism of conventional drugs used for treating IBD, such as corticosteroid and 5-aminosalicylic acid, involves the inhibition of NF-kB signaling in IECs (Auphan et al, 1995;McGovern et al, 2010). Recently, ER stress in IECs was proposed as a cause or consequence of IBD (Kaser and Blumberg, 2010). Interestingly, a previous report demonstrated that an increase in misfolded or unfolded proteins resulted in the activation of NF-kB signaling (Pahl and Baeuerle, 1995).…”

“…ER stress results from any situation that causes the accumulation of misfolded or unfolded proteins within the ER. When misfolded or unfolded proteins accumulate within the ER, UPR signaling is initiated, which leads to the activation of three ER transmembrane proteins, including inositol-requiring enzyme, pancreatic ER kinase, and activating transcription factor-6 (Kaser and Blumberg, 2010). Thereby, the expansion of its protein-folding function leads to attenuation of the accumulation of misfolded or unfolded proteins.…”