Unfolded protein responses in the intestinal epithelium: sensors for the microbial and metabolic environment

In inflammatory bowel disease, the intestinal microbiota is a key driver of inflammation. Hence, efficient sensing of luminal antigens and subsequent initiation of adequate immune responses is crucial for maintaining homeostasis, particularly in intestinal epithelial cells. Pathways such as Toll-like receptor-mediated signaling and autophagy sense microbial products to activate inflammatory processes and, concomitantly, interact with cellular stress responses such as the unfolded protein response (UPR). Proteostasis is particularly sensitive toward environmental challenges and triggers, such as oxidative stress and metabolic alterations, and impact protein folding in different cellular compartments. In contrast, disturbances in energy supply including impaired mitochondrial function and epithelial β-oxidation have been suspected to contribute toward intestinal inflammation. Interestingly, the 2 main organelles linking metabolic pathways, inflammatory signaling and pathogen-sensing, endoplasmic reticulum (ER) and mitochondria (mt), can trigger distinct UPRs, and both ER UPR and mt UPR have been shown to be disease-relevant in inflammatory bowel disease. The ER is essential for the coordination of metabolic responses through controlling the synthetic and catabolic pathways of various nutrients and furthermore, ER UPR signaling directly intersects with inflammation-associated NF-κB and Toll-like receptor pathways. Consistently, next to their function in cellular energy supply, mitochondria are increasingly recognized as integrators of immune responses. For instance, mitochondria participate in innate immunity to viral infection through the pattern recognition receptor retinoic acid inducible gene-I and are involved in inflammasome activation. Thus, we hypothesize that a concerted UPR activation might represent an innate mechanism to sense potentially threatening changes of the mucosal metabolic environment and impacts host cellular functions and immune responses.