Non-hematopoietic STAT6 induces 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 a greater risk for developing colorectal cancer. STAT6 activation was detected in inflamed colonic epithelium of active IBD patients, suggesting a role of epithelial STAT6 in colitis development. Here, we demonstrated that non-hematopoietic STAT6, but not hematopoietic STAT6, triggered DSS-induced colitis and subsequent tumorigenesis. This could be due to the enhancingeffect of STAT6 on gut permeability and microbiota translocation via interruption of epithelial tight junction integrity. Mechanistically, long-myosin light-chain kinase (MLCK1) was identified as a target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Furthermore, neutralization of IL-13, which was primarily derived from type 2 innate lymphoid cells (ILC2) in a microbiota-dependent way, inhibited epithelial STAT6 activation and improved gut permeability and DSSinduced colitis. Importantly, pharmacological inhibition of STAT6 reduces murine intestinal tumor formation, and tumoral p-STAT6 levels positively correlated to the clinical stage and poor prognosis of human colorectal cancer. Thus, our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity and colitis development, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer.

Beyond Immunity: Underappreciated Functions of Intestinal Macrophages

“…Co-culturing IECs with alternatively activated murine MPs increased their levels of nuclear β-catenin through a STAT6-dependent pathway from MPs ( 138 , 139 ). Conversely, deletion of STAT6 in epithelial cells drastically impaired CD206 + MP numbers in the colonic LP, altered epithelial repair, and exacerbated tissue damage, suggesting a possible STAT6-dependent circuit for both epithelial cell proliferation and MP activation ( 140 ). Hepatocyte growth factor (HGF) is growth factor that aids in the eMP-IEC interactions and was reported to be produced by human and murine MPs to promote the growth of epithelial cell lines in vitro , independent of direct MP-epithelial cell contact.…”

Acai berry extract as a regulator of intestinal inflammation pathways in a Caco‐2 and RAW 264.7 co‐culture model

“…The integrity of the gut barrier is partially contributed by intercellular protein groups, tight junction (TJ) complexes, and cytoskeleton microtubules and filamentum that retain strong intercellular links between the epithelial cells (Almousa et al., 2018). TJs are important for maintaining intestinal homeostasis by modulating paracellular permeability, which serves as a structural and functional defense (Lin et al., 2019). A lot of pro‐inflammatory cytokines results from an increment in intestinal permeability and a mucosal immune system that is immoderately exposed to pathogens when the epithelial monolayer and the production of altered mucus are impaired.…”

The Regulation of Intestinal Inflammation and Cancer Development by Type 2 Immune Responses

“…In the DSS model, ILC2 was described as a major source of IL-13. In this study, IL-13 contributed to gut permeability and intestinal inflammation via activation of STAT6 and subsequent dysregulation of tight junctions through upregulation of myosin light chain kinase 1 (MLCK1) [68]. However, the conclusion of a pro-inflammatory role of ILC2 is in contradiction with another study, in which the role of IL-33 in the pathogenesis of IBD was analyzed.…”