Toll-like receptor signalling via IRAK4 confers epithelial integrity and tightness through regulation of junctional tension

Abstract

Toll-like receptors (TLRs) in mammalian systems are well characterised for their role in innate immunity. In addition, TLRs also fulfil crucial functions outside immunity, including the dorso-ventral patterning function of the original Toll receptor in Drosophila and neurogenesis in mice. Recent discoveries in flies suggested key roles for TLRs in epithelial cells in patterning of cytoskeletal activity near epithelial junctions. Here we address the function of TLRs and the downstream key signal transduction component IRAK4 (interleukin-1 receptor associated kinase 4) in human epithelial cells. Using differentiated human Caco-2 cells as a model for the intestinal epithelium, we show that these cells exhibit baseline TLR signalling as revealed by p-IRAK4 and that blocking IRAK4 function leads to a loss of epithelial tightness involving key changes at tight junctions and adherens junctions. These changes correlate with a loss of epithelial tension and changes in junctional actomyosin. Knock-down of IRAK4 and certain TLRs phenocopies the inhibitor treatment. These data suggest a model whereby TLR receptors near epithelial junctions might be involved in a continuous sensing of the epithelial state to promote epithelial tightness and integrity.