Abstract
Disturbance of epithelial barrier function causes chronic intestinal inflammation such as inflammatory bowel disease. Several studies have reported that Th2 cytokines such as interleukin (IL)-4 and IL-13 play an important role in the regulation of intestinal barrier function. However, the precise role of the IL-4 receptor α subunit (IL-4Rα) in intestinal inflammation remains unclear. Thus, we used an experimental colitis model to investigate the role of IL-4Rα in intestinal inflammation. IL-4Rα-deficient (IL-4Rα-/-) mice and their littermate wild-type (WT) mice were used. Experimental colitis was induced by administration of 3% dextran sulfate sodium (DSS) in the drinking water for seven days. Treatment with DSS caused body weight loss, an increase in the disease activity index and histological abnormalities in WT colitis mice, all of which were significantly attenuated in IL-4Rα-/- colitis mice. Neutrophil infiltration in the colonic mucosa was reduced in IL-4Rα-/- colitis mice compared with WT colitis mice. NADPH oxidase 1 expression and reactive oxygen species production were increased in the colons of IL-4Rα-/- mice. Furthermore, elevated intestinal permeability induced by DSS treatment was suppressed in IL-4Rα-/- colitis mice. These results demonstrate that IL-4Rα-/- mice exhibit reduced susceptibility to DSS-induced colitis. Our present findings suggest that IL-4Rα deficiency enhances intestinal mucosal barrier function through the upregulation of NADPH oxidase 1-dependent reactive oxygen species production, thereby suppressing the development of intestinal inflammation.
Highlights
The intestinal mucosa forms a selective barrier that simultaneously allows nutrient absorption and limits the uptake of antigens from the lumen (Quiros and Nusrat, 2019)
To determine the role of IL-4 receptor α subunit (IL-4Rα) in intestinal inflammation, we examined the development of dextran sulfate sodium (DSS)-induced acute colitis in WT and IL-4Rα-/- mice
Our results indicate that the development of DSS-induced colitis is alleviated in IL-4Rα-/- mice through enhancement of NOX1derived reactive oxygen species (ROS) production in the colon
Summary
The intestinal mucosa forms a selective barrier that simultaneously allows nutrient absorption and limits the uptake of antigens from the lumen (Quiros and Nusrat, 2019). Intestinal mucosal barriers include physical barriers, such as the mucus layer, glycocalyx and cell junctions, and chemical barriers, such as antimicrobial peptides and proteins of the regenerating islet-derived three family, these barriers are regulated by intestinal environmental factors and cellular networks including epithelial cells, mesenchymal cells, immune cells and neuronal cells Breakdown of the intestinal mucosal barrier plays a pivotal role in the pathogenesis of intestinal immune-related disorders such as infectious colitis and inflammatory bowel disease (IBD) (Okumura and Takeda, 2017; Hayashi, 2020). Reductions in mucus production and antimicrobial peptide levels have been reported in IBD patients (Wehkamp et al, 2002; Swidsinski et al, 2007). Mice genetically deficient in mucosal barrier components showed high sensitivity to intestinal inflammation (Johansson et al, 2008)
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