STAT6 Induces MLCK1-Dependent Epithelial Tight Junction Dysfunction and Promotes Intestinal Inflammation and Tumorigenesis

Abstract

Enhanced gut permeability due to dysregulated epithelial tight junction is often associated with inflammatory bowel diseases (IBD), which have greater risk for developing colorectal cancer. We demonstrated that non-hematopoietic STAT6 was able to enhance gut permeability and microbiota translocation to induce excessive colonic inflammation that facilitates tumorigenesis. We identified IL-13 as the upstream activator of epithelial STAT6 to mediate colonic inflammation and type 2 innate lymphoid cells (ILC2) as the major source of IL-13 in a microbiota-dependent way. Mechanistically, long myosin light chain kinase (MLCK1) was identified as a transcriptional target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Moreover, STAT6 inhibitor efficiently inhibited intestinal tumor development. Our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity, which could be a causal factor for colonic inflammation, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer.