P0094 The Role Of Sdf2l1 On Intestinal Physiology And Inflammatory Bowel Disease

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Abstract Background The intestinal tract, as the body's largest mucosal surface, is exposed to various factors, requiring specialized epithelial and immune cell interactions to maintain homeostasis. These interactions, along with a dynamic microenvironment, induce endoplasmic reticulum (ER) stress. While the ER employs coping mechanisms to preserve cellular integrity, unresolved ER stress is a key driver in the development and progression of chronic inflammatory bowel disease (IBD).1 An important player in the ER-resident unfolded protein response is stromal derived growth factor 2-like 1 (Sdf2l1), a chaperone protein that ensures proper protein folding and prevents the accumulation of misfolded proteins.2,3 Furthermore, Sdf2l1 is highly expressed in the intestine, thus we hypothesize that Sdf2l1 plays a pivotal role in the pathogenesis of IBD. Methods To investigate the role of Sdf2l1 in the gastrointestinal system, we used wildtype or conditional Sdf2l1 knockout mice lacking Sdf2l1 in intestinal epithelial cells (Sdf2l1ΔIE) and ex vivo organoid systems. Results No baseline differences were found in the intestinal mucosa of Sdf2l1-deficient mice, but molecular differences in ER stress responses were evident in small intestinal organoids. When ER stress was induced with IL-22, Sdf2l1ΔIE organoids showed significantly higher NFκB expression, suggesting enhanced UPR activation or compromised stress coping. Under tunicamycin treatment, Sdf2l1-deficient organoids had increased Hspa5/Grp78 expression, indicating elevated ER stress. Sdf2l1 is needed for proper UPR initiation, as it forms a complex with GRP78. In these deficient organoids, IRE1 signaling was impaired, as shown by reduced Xbp1s expression. Conclusion Insufficient activation of the UPR due to Sdf2l1 deficiency and the associated ER stress potentially leads to inflammatory reactions in the cells. Impaired cell integrity disrupts intestinal homeostasis and can lead to an imbalance of pro- and anti-inflammatory processes, thus favoring the pathophysiology of IBD.