Transgenic overexpression of ITGB6 in intestinal epithelial cells exacerbates dextran sulfate sodium‐induced colitis in mice

Abstract

Integrins, as a large family of cell adhesion molecules, play a crucial role in maintaining intestinal homeostasis. In inflammatory bowel disease (IBD), homeostasis is disrupted. Integrin αvβ6, which is mainly regulated by the integrin β6 subunit gene (ITGB6), is a cell adhesion molecule that mediates cell‐cell and cell‐matrix interactions. However, the role of ITGB6 in the pathogenesis of IBD remains elusive. In this study, we found that ITGB6 was markedly upregulated in inflamed intestinal tissues from patients with IBD. Then, we generated an intestinal epithelial cell‐specific ITGB6 transgenic mouse model. Conditional ITGB6 transgene expression exacerbated experimental colitis in mouse models of acute and chronic dextran sulphate sodium (DSS)‐induced colitis. Survival analyses revealed that ITGB6 transgene expression correlated with poor prognosis in DSS‐induced colitis. Furthermore, our data indicated that ITGB6 transgene expression increased macrophages infiltration, pro‐inflammatory cytokines secretion, integrin ligands expression and Stat1 signalling pathway activation. Collectively, our findings revealed a previously unknown role of ITGB6 in IBD and highlighted the possibility of ITGB6 as a diagnostic marker and therapeutic target for IBD.

Integrin β6 deficiency protects mice from experimental colitis and colitis-associated carcinoma by altering macrophage polarization

“…found that the level of serum IgG anti-integrin αvβ6 autoantibodies was obviously increased in patients with UC ( 23 ), consistent with our finding that integrin αvβ6 was abundantly expressed in the intestinal epithelium of UC. We also found integrin αvβ6 expression was related with the severity of inflammation, in accordance with the previous report which through ITGB6 transgenic mouse model found that integrin β6 maintained the colon hyperresponsive to inflammatory factors and ultimately promoted the development of IBD ( 10 ). What’s more, we observed that the expression of integrin β6 was elevated in other inflammatory organ tissues such as gastritis, pancreatitis and pneumonitis, which verified that integrin β6 could be de novo synthesized in inflammatory events with tissue remodeling.…”

“…Acute colitis was induced in WT and ITGB6-KO mice by feeding drinking water dissolved with a concentration of 2.5% DSS (MP Biomedicals) for 7 days. Body weight, fecal concentration and rectal bleeding were recorded once a day which constitute the disease activity index (DAI) ( 10 ). The DAI score was obtained by summing the scores for weight loss, fecal concentration and degree of blood in the stool (range 0-12).…”

Targeting integrin pathways: mechanisms and advances in therapy

“…ITGB6 transgenic mice were found to have increased susceptibility to both acute and chronic dextran sulfate sodium-induced colitis, and αvβ6 induces intestinal fibrosis through the FAK/AKT pathway. 508 , 509 …”

“…ITGB6 transgenic mice were found to have increased susceptibility to both acute and chronic dextran sulfate sodium-induced colitis, and αvβ6 induces intestinal fibrosis through the FAK/AKT pathway. 508,509 Anti-inflammatory treatment is ineffective in the development of fibrosis in IBD, a consequence of chronic inflammation. The mechanism of fibrosis is thought to be a continuous interaction between the stiffened ECM matrix resulting from the aberrant release of ECM components and cellular compartments.…”