Knockdown of Ste20-like proline/alanine-rich kinase (SPAK) attenuates intestinal inflammation in mouse (54.9)

Abstract

Abstract Inflammatory bowel diseases (IBDs), principally Crohn’s disease and ulcerative colitis, are characterized by epithelial barrier disruption and alterations in immune regulation. Ste20-like proline/alanine-rich kinase (SPAK) plays a role in intestinal inflammation, but its underlying mechanisms need to be defined. SPAK KO mice exhibited significant increases of intestinal barrier function. Knock-down of SPAK significantly decreased paracellular intestinal permeability to FITC-dextran, and lowered significantly the sodium ion selectivity of tight junctions in intestinal epithelial cells. Further, the expression of junction proteins β-catenin, claudin-2 decreased. In contrast, expression of ZO-1, Occludin, E-cadeherin increased significantly, whereas the change of expressions of Claudin-4 and Claudin-1 was not noticeable. In vivo studies using mouse model of colitis induced by dextran sulfate sodium (DSS) and trinitrobenzene sulfuric acid (TNBS) showed that KO mice were more tolerant to DSS or TNBS treatment than wild-type animals, as demonstrated by clinical and histological characteristics and MPO enzymatic activities. KO mice also demonstrated ameliorated colon inflammation by mouse endoscopy compared to wild type mice. Consistent with this notion, we found that SPAK knockdown attenuated the increases of inflammatory cytokines production in vivo and also ameliorated bacterial translocation under DSS treatment, which together likely reduce intestinal epithelial permeability.