Non-hematopoietic STAT6 induces epithelial tight junction dysfunction and promotes intestinal inflammation and tumorigenesis

Abstract

Increased gut permeability, caused by dysregulated epithelial tight junctions, is commonly linked to inflammatory bowel diseases (IBD), which carry a higher risk of developing colorectal cancer. STAT6 activation has been observed in the inflamed colonic epithelium of patients with active IBD, indicating a possible role of epithelial STAT6 in the progression of colitis. In this study, we demonstrated that non-hematopoietic STAT6, but not hematopoietic STAT6, triggered DSS-induced colitis and subsequent tumor development. This effect may be due to STAT6′s role in enhancing gut permeability and promoting microbiota translocation by disrupting epithelial tight junction integrity. Mechanistically, long-myosin light-chain kinase (MLCK1) was identified as a target of STAT6, leading to tight junction dysfunction and microbiota-driven colitis. Additionally, neutralizing IL-13, primarily derived from type 2 innate lymphoid cells (ILC2) in a microbiota-dependent manner, inhibited epithelial STAT6 activation, improved gut permeability, and alleviated DSS-induced colitis. Notably, pharmacological inhibition of STAT6 reduced intestinal tumor formation in mice, and high levels of tumoral p-STAT6 were correlated with advanced clinical stages and poor prognosis in human colorectal cancer. Therefore, our study highlights the direct role of STAT6 in compromising epithelial tight junction integrity and driving colitis development, suggesting that STAT6 could be a promising therapeutic and preventive target for IBD and colitis-associated AS1517499 cancer.