Epithelial MLCK deficiency alleviates alcohol-associated liver disease via dendritic–Th17 cell axis

BACKGROUND & AIMS: Intestinal dendritic cells (DCs) play a key role in immune regulation, especially during injury. The role of intestinal epithelial paracellular permeability in DCs antigen presentation and its regulation is unclear. Myosin light-chain kinase (MLCK) regulates barrier permeability, and this study examines its role in DCs function and immune responses in alcohol-associated liver disease (ALD). METHODS: -dependent MLCK activation, while also evaluating tight junction integrity, DC antigen uptake and presentation by flow cytometry, and pathogenic Th17 cell responses (n = 3). RESULTS: /CaM-dependent pathways, disrupted tight junctions, and enhanced DC antigen uptake and antigen-presenting capacity (by 1.4-fold, n = 3, p < 0.05). This promoted pathogenic Th17 cell responses and GM-CSF production (by 2-fold, n = 6, p < 0.05) associated with liver inflammation. CONCLUSIONS: This study highlights the role of MLCK-regulated intestinal permeability in DCs function and Th17 cells differentiation in ALD. Targeting this pathway may provide new therapeutic strategies for ALD. IMPACT AND IMPLICATIONS: This study reveals the crucial role of MLCK-regulated intestinal paracellular permeability in alcohol-associated liver disease (ALD), expanding our understanding of the gut-liver interaction. The findings provide new scientific insights into immune regulation and barrier function, offering potential therapeutic implications for the treatment of ALD. By highlighting the role of MLCK-mediate barrier function in dendritic cells (DCs) function and Th17 cells differentiation, this research opens up new avenues for clinical application, particularly in developing targeted therapies for ALD. For researchers, these findings offer a fresh perspective on the interplay between the gut microbiota and immune responses, advancing the field of immunology and gastrointestinal diseases.