Abstract
The intestinal tract encompasses the largest mucosal surface fortified with a fine layer of intestinal epithelial cells along with highly sophisticated network of the lamina propria immune cells that are indispensable to sustain gut homeostasis. However, it can be challenging to uphold homeostasis when these cells in the intestine are perpetually exposed to insults of both endogenous and exogenous origin. The complex networking and dynamic microenvironment in the intestine demand highly functional cells ultimately burdening the endoplasmic reticulum (ER) leading to ER stress. Unresolved ER stress is one of the primary contributors to the pathogenesis of inflammatory bowel diseases (IBD). Studies also suggest that ER stress can be the primary cause of inflammation and/or the consequence of inflammation. Therefore, understanding the patterns of expression of ER stress regulators and deciphering the intricate interplay between ER stress and inflammatory pathways in intestinal epithelial cells in association with lamina propria immune cells contribute toward the development of novel therapies to tackle IBD. This review provides imperative insights into the molecular markers involved in the pathogenesis of IBD by potentiating ER stress and inflammation and briefly describes the potential pharmacological intervention strategies to mitigate ER stress and IBD. In addition, genetic mutations in the biomarkers contributing to abnormalities in the ER stress signaling pathways further emphasizes the relevance of biomarkers in potential treatment for IBD.
Highlights
The intestine houses a plethora of innocuous microbes that establish a symbiotic relationship in the host
Defective expression of unfolded protein response (UPR) genes, Defective recruitment of secretory protein coding mRNAs into the endoplasmic reticulum (ER) leading to compromised protein secretion [45] Diminished expression of ER chaperones BiP and P58IPK, C/EBP Homologous Protein (CHOP) – induced apoptosis [46, 47] Impaired granule exocytosis pathway in Paneth cells [48], increased ATF6a activity [49] and IL-22 induced TNF expression leading to necroptosis [50]
Recent studies conducted on Necrotizing Enterocolitis (NEC) mouse models showed that Tauroursodeoxycholic Acid (TUDCA) is capable of reducing the ER stress markers and apoptosis by inhibiting Protein Kinase R–Like ER Kinase (PERK)-Eukaryotic Initiation Factor 2a (eIF2a) via activation of the Phosphatidylinositol 3–kinase (PI3K)/ Akt pathway [84]
Summary
The intestine houses a plethora of innocuous microbes that establish a symbiotic relationship in the host. Under ER stress, the BiP dissociates, activating IRE1a, PERK, and ATF6 signaling cascades to salvage the distressed cell. Overall activation of PERK inhibits eukaryotic translation, prevents the accumulation of unfolded proteins that promote inflammatory gene expression, and regulates apoptosis through ATF4.
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