Interleukin-4 Receptor α Subunit Deficiency Alleviates Murine Intestinal Inflammation In Vivo Through the Enhancement of Intestinal Mucosal Barrier Function (1)

Intestinal mucosal barriers include not only physical barriers, such as the mucus layer, glycocalyx and cell junctions, but also 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. IL-4 and IL-13 play a role in the regulation of intestinal mucosal barrier functions. The role of IL-4Rα in intestinal mucosal inflammation was investigated using a model of dextran sulfate sodium (DSS)-induced colitis in IL-4Rα-deficient (IL-4Rα-/-) mice.

IL-4Rα-/- mice on a BALB/c background were treated with 3% DSS in their drinking water for seven day to induce an experimental colitis model. On day 4 after DSS treatment via the drinking water, a decrease in body weight was observed in WT colitis mice but was significantly suppressed in IL-4Rα-/- mice as well as the average of the diarrhea score and rectal bleeding score and was significantly attenuated in IL-4Rα-/- colitis mice compared with WT colitis mice.

The number of infiltrated neutrophils expressing MPO in the colonic mucosa of IL-4Rα-/- colitis mice was dramatically reduced compared to that in WT colitis mice.

The FITC-dextran level in the plasma of WT colitis mice was significantly elevated on day 7. The elevated FITC-dextran level was markedly decreased in the IL-4Rα-/- colitis mice. The level of plasma FITC-dextran was significantly lower in IL-4Rα-/- normal mice than in WT normal mice.

IL-4Rα Deficiency Increases NADPH Oxidase 1 (NOX1)-Dependent Reactive Oxygen Species (ROS) Production in the Mouse Colon. The production of ROS was significantly increased in the colons of IL-4Rα-/- normal mice compared with WT normal mice.

Neutrophil infiltration in the mucosa is mediated by specific chemoattractants such as CXCL1, CXCL2 (also known as macrophage inflammatory protein 2; MIP2) and CXCL8. Among these cytokines, IL-1β exhibits increased production in the model of DSS-induced colitis. In fact, the infiltration of neutrophils and the upregulation of CXCL2 and IL-1β observed in colonic tissues of colitis mice were significantly suppressed in the IL-4Rα-/- mice.

IL-10-deficient mice are well known as a model of spontaneous colitis because IL-10 secreted from intestinal macrophages plays a pivotal role in the regulation of intestinal homeostasis during host defense. Mice with combined deficiency of NOX1 and IL-10 exhibited colitis symptoms earlier than IL-10-deficient mice. Administration of apocynin, an antioxidant and a nonselective NADPH inhibitor, suppressed the inflammatory response in a model of DSS- and tumor necrosis factor-α-induced colitis.

Intestinal epithelial cells cover the outermost surface of the mucosa and interface with the lamina propria to form the intestinal mucosal barrier. Thus, NOX1-dependent ROS production in intestinal epithelial cells is considered an important property for maintaining intestinal barrier integrity.

1. A. Hertati, S. Hayashi, Y. Ogawa, T. Yamamoto, M. Kadowaki, Interleukin-4 Receptor α Subunit Deficiency Alleviates Murine Intestinal Inflammation In Vivo Through the Enhancement of Intestinal Mucosal Barrier Function. Frontiers in Pharmacology. 11 (2020), , doi:10.3389/fphar.2020.573470.