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Role of ER Stress Mediated Unfolded Protein Responses and ER Stress Inhibitors in the Pathogenesis of Inflammatory Bowel Disease

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Abstract

Previous investigations have increased the knowledge about the pathological processes of inflammatory bowel diseases. Besides the complex organization of immune reactions, the mucosal epithelial lining has been recognized as a crucial regulator in the commencement and persistence of intestinal inflammation. As the intestinal epithelium is exposed to various environmental factors, the intestinal epithelial cells are confronted with diverse cellular stress conditions. In eukaryotic cells, an imbalance in the endoplasmic reticulum (ER) might cause aggregation of unfolded or misfolded proteins in the lumen of ER, a condition known as endoplasmic reticulum stress. This cellular mechanism stimulates the unfolded protein response (UPR), which elevates the potential of the endoplasmic reticulum protein folding, improves protein production and its maturation, and also stimulates ER-associated protein degradation. Current analyses reported that in the epithelium, the ER stress might cause the pathogenesis of inflammatory bowel disease that affects the synthesis of protein, inducing the apoptosis of the epithelial cell and stimulating the proinflammatory reactions in the gut. There have been significant efforts to develop small molecules or molecular chaperones that will be potent in ameliorating ER stress. The restoration of UPR balance in the endoplasmic reticulum via pharmacological intervention might be a novel therapeutic approach for the treatment of inflammatory bowel diseases (IBDs). This review provides novel insights into the role of chemical chaperone UPR modulators to modify ER stress levels. We further discuss the future directions/challenges in the development of therapeutic strategies for IBDs by targeting the ER stress.

Graphical Abstract

Figure depicting the role of endoplasmic reticulum stress-mediated inflammatory bowel disease and the therapeutic role of endoplasmic reticulum stress inhibitors in alleviating the diseased condition.

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Acknowledgments

The authors thank Chettinad Academy of Research and Education (CARE) for providing the financial support and SERB, DST, Government of India, and CARE for providing infrastructural support to complete this work.

Funding

This work was supported by grants to Dr. Antara Banerjee (PI) from the SERB-DST, Government of India, file no ECR/2017/001066, and DST Inspire research student grant with award number 190963.

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Authors and Affiliations

  1. Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India

    Dikshita Deka, Alakesh Das, Surajit Pathak & Antara Banerjee

  2. Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35128, Padua, Italy

    Renata D’Incà & Giacomo Carlo Sturniolo

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  1. Dikshita Deka
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Contributions

AB designed the study and conceptualized the work. AB, DD, AD conducted data analysis and wide-ranging aspects of the manuscript preparation and pictorial representations. RD, GCS, SP critically reviewed the draft manuscript and provided feedback on data analyses. All authors read and approved the final manuscript.

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Correspondence to Antara Banerjee.

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Deka, D., D’Incà, R., Sturniolo, G.C. et al. Role of ER Stress Mediated Unfolded Protein Responses and ER Stress Inhibitors in the Pathogenesis of Inflammatory Bowel Disease. Dig Dis Sci 67, 5392–5406 (2022). https://doi.org/10.1007/s10620-022-07467-y

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