Cytokine IL9 Triggers the Pathogenesis of Inflammatory Bowel Disease Through the miR21-CLDN8 Pathway

Background Cytokine interleukin-9 (IL9) plays an essential role in the pathogenesis of inflammatory bowel disease. However, the molecular mechanism underlying the IL9 pathway remains unknown. Here, we initiate a series of studies to characterize the essential components of this pathway. Methods The expression of IL9 in colon biopsies from Crohn's disease (CD) and controls were examined by quantitative polymerase chain reaction, immunoblot, and immunohistochemistry. The trinitrobenzene sulfonic acid (TNBS)-induced colitis model was used to verify the therapeutic efficiency of anti-IL9 mAb. Bioinformatics analysis was performed to predict putative candidate microRNAs that mediate the crosstalk between the IL9 proinflammatory signal and the downstream target gene in intestinal barrier function. Caco-2, NCM460, and SW480 cells were used to assess the specific pathway in vitro. Results We demonstrated the proinflammatory role of IL9 in the colonic mucosa of patients with CD. The junction complex protein Claudin 8 (CLDN8) was identified as a critical downstream component of the IL9 inflammatory cascade. Anti-IL9 treatment alleviated TNBS-induced colitis by restoring CLDN8 levels in the colonic mucosa. Notably, we characterized miR21 as a critical player that mediates the crosstalk between the proinflammatory IL9 and the downstream CLDN8 in both in vitro and in vivo models. Conclusions Our results, for the first time, uncover a critical role of miR21 and CLDN8 in the complex network that IL9 regulates the intestinal epithelium barrier in the pathogenesis of CD. Interventional blockade of the IL9-miR21-CLDN8 pathway could be a novel therapeutic approach for the management of CD.