Association of GILZ with MUC2, TLR2, and TLR4 in Inflammatory Bowel Disease

Abstract

Ulcerative colitis (UC) and Crohn’s Disease (CD) are chronic relapsing inflammatory diseases that are caused by genetic, environmental, and immune factors. Treatment strategies are currently based on symptomatic control by immunosuppression. The glucocorticoid-induced leucine zipper (GILZ), a mediator of several effects of glucocorticoids, was recently found to be secreted by goblet cells and play a role in inflammatory bowel disease (IBD). This study investigates which genes GILZ is associated with in its role in intestinal barrier functions. We examined datasets from the Gene Expression Omnibus (GEO) and ArrayExpress profiles of the gut of healthy subjects (HSs), as well as UC and CD patients. The human colonic epithelial HT29 cell line was used for in vitro validation experiments. GILZ was significantly correlated with MUC2, TLR2, and TLR4. In particular, an inverse correlation was found between the GILZ and MUC2 in HS and patients with IBD, mostly in those with an active disease. Further, direct pairwise correlations for GILZ/TLR2 and GILZ/TLR4 were found in HSs and UC patients, but not in CD patients. Overall, our results reveal the crosstalk at the transcription level between the GILZ, MUC2, and TLRs in the mucosal barrier through common pathways, and they open up new perspectives in terms of mucosal healing in IBD patients.

Fundamental transport mechanism of mucin-2 ER-to-Golgi trafficking identifies source of ER stress in inflammatory bowel disease

“…This was attributed to different origins of the disease, be it genetic or environmental, analysis methods and even patient cohort demographics (as reviewed in (Bankole et al , 2021)). However, multiple studies agreed on an increase in MUC2 mRNA in UC and CD which was exacerbated in inflamed regions matching our findings (Ahn et al ., 2005; Cari et al , 2023; Gersemann et al , 2009; Hanski et al , 1999; Heazlewood et al ., 2008). Furthermore, this human data confirms our earlier conclusions that increased expression levels of mucin-2 are concomitant with increased levels of SEC31A, cTAGE5 and TANGO1, signifying their association.…”

“…The increased mRNA levels could be an indicator of its regulatory role in mucosal immunity to actively reduce inflammatory responses (Hatamzade Esfahani & Day, 2023; Sedda et al ., 2015). We propose that increased TGF-β1 concurrent with high MUC2 mRNA expression and trafficking signaled by SEC31A, cTAGE5 and TANGO1 levels could reflect efforts to start reparative processes to restore the broken mucosal barrier (Cari et al ., 2023; Ihara et al ., 2016).…”

Inflammatory Bowel Diseases: Does One Histological Score Fit All?

“…Both in UC and CD, it resulted in an impaired active disease, while it was restored in quiescent disease, thus, correlating with neutrophil infiltration and epithelial injury [ 59 ]. Moreover, it was also found to be directly related to MUC2, one of the major components of the mucus barrier, as well as to TLR2 and TLR4, which are involved in several gut mucosal functions, including permeability [ 60 ]. Recently, GILZ has gained attention in IBDs as it negatively modulates neutrophil activation, thereby promoting a negative control in the main cellular effector of disease activity in IBD [ 61 , 62 ].…”

Paneth Cell, Gut Microbiota Dysbiosis and Diabetes Mellitus

“…Both the structural integrity and normal physiological function of the small intestine are dependent on the continuous generation of new IECs by the Lgr5 + ISCs to replace senescent ones [2,[61][62][63][64]. A combination of the surface epithelial cells and junctional proteins provides a continuous physical barrier that is augmented by mucins [5,7]. The microbiota of the gut is also critical for the development and sustenance of the innate immunity of the small intestine [65][66][67][68][69][70].…”

“…The intestinal epithelial cells (IECs), junctional proteins and microbiota are responsible for the innate immunity of the small intestine [3,[5][6][7]. Among the IECs that participate in the innate immunity of the small intestine are the absorptive enterocytes, goblet cells, Paneth cells, enteroendocrine cells, tuft cells and microfold cells (M-cells) [2,8].…”