Leptin Downregulates Angulin-1 in Active Crohn’s Disease via STAT3

Abstract

Crohn’s disease (CD) has an altered intestinal barrier function, yet the underlying mechanisms remain to be disclosed. The tricellular tight junction protein tricellulin is involved in the maintenance of the paracellular macromolecule barrier and features an unchanged expression level in CD but a shifted localization. As angulins are known to regulate the localization of tricellulin, we hypothesized the involvement of angulins in CD. Using human biopsies, we found angulin-1 was downregulated in active CD compared with both controls and CD in remission. In T84 and Caco-2 monolayers, leptin, a cytokine secreted by fat tissue and affected in CD, decreased angulin-1 expression. This effect was completely blocked by STAT3 inhibitors, Stattic and WP1066, but only partially by JAK2 inhibitor AG490. The effect of leptin was also seen at a functional level as we observed in Caco-2 cells an increased permeability for FITC-dextran 4 kDa indicating an impaired barrier against macromolecule uptake. In conclusion, we were able to show that in active CD angulin-1 expression is downregulated, which leads to increased macromolecule permeability and is inducible by leptin via STAT3. This suggests that angulin-1 and leptin secretion are potential targets for intervention in CD to restore the impaired intestinal barrier.

JAK-STAT Pathway Regulation of Intestinal Permeability: Pathogenic Roles and Therapeutic Opportunities in Inflammatory Bowel Disease

“…In a recent study, localization of tricellulin was found to be shifted predominantly from intestinal crypts to the surface epithelium in CD patients [ 66 ]. A key regulator of tricellulin localization, angulin-1, was also discovered to be downregulated in active CD [ 67 ]. Intriguingly, leptin, a hormone that is primarily produced by adipose tissue to regulate appetite and food storage, is able to downregulate angulin-1 levels in T84 and Caco-2 cell lines [ 67 ].…”

“…A key regulator of tricellulin localization, angulin-1, was also discovered to be downregulated in active CD [ 67 ]. Intriguingly, leptin, a hormone that is primarily produced by adipose tissue to regulate appetite and food storage, is able to downregulate angulin-1 levels in T84 and Caco-2 cell lines [ 67 ]. Adipose tissue is commonly seen adjacent to the inflamed intestinal segments in CD and could be a potential source of leptin [ 68 ].…”

“…Adipose tissue is commonly seen adjacent to the inflamed intestinal segments in CD and could be a potential source of leptin [ 68 ]. Caco-2 cells treated with leptin exhibited increased intestinal permeability as demonstrated by elevated FD4 flux [ 67 ]. These effects were negated by pre-treatment with inhibitors of STAT3, Stattic and WP1006, and partially by the JAK2 inhibitor AG490 [ 67 ].…”

“…Caco-2 cells treated with leptin exhibited increased intestinal permeability as demonstrated by elevated FD4 flux [ 67 ]. These effects were negated by pre-treatment with inhibitors of STAT3, Stattic and WP1006, and partially by the JAK2 inhibitor AG490 [ 67 ]. These findings reveal leptin as a novel target for the development of JAK-STAT inhibitors to alleviate defects in the intestinal barrier.…”

Editorial: Loss of Epithelial Barrier Integrity in Inflammatory Diseases: Cellular Mediators and Therapeutic Targets

“…For example, the recognized capacity of anti-TNF therapy to restore the pathologically increased rate of apoptotic IECs and the subsequent loss of epithelial resistance in IBD patients (21), as well as the counteracting influence of azathioprine and 5-aminosalicylic acid on the inflammation-triggered downregulation and rearrangement of junctional proteins in in vitro cultured IECs and intestinal organoids (22). In addition, defined molecular mediators and intracellular signaling pathways involved in the maintenance of the epithelial tightness (e.g., STAT6, angulin-1, leptin, RhoA, and IL13Rα2) (23)(24)(25)(26), in IEC survival (e.g., Caspase-8) (27), in the production of antimicrobial peptides (e.g., human β-defensin 2) (28) and in wound healing (e.g., STAT1, STAT3) (29,30) have also been suggested as innovative therapeutic targets. As exemplarily demonstrated by Gerbeth et al summarizing the multiple effects of histone deacetylase inhibitors on gut homeostasis, it will in general be essential to always consider the above outlined cellular complexity of the protective mucosal barrier and carefully validate the role of potential innovative target structures for the entire panel of involved cell types.…”