Toll-like receptor signalling via IRAK4 affects epithelial integrity and tightness through regulation of junctional tension.
| Autor: | Peterson J; MRC-Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK., Balogh Sivars K; Oncology R&D, Precision Medicine and Biosamples, R&D, AstraZeneca, Pepparedsleden 1, Nova, Mölndal, SE-431 83, Sweden., Bianco A; Clinical Pharmacology and Safety Sciences CPSS Oncology Safety, AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK., Röper K; MRC-Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. |
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| Jazyk: | angličtina |
| Zdroj: | Development (Cambridge, England) [Development] 2023 Dec 15; Vol. 150 (24). Date of Electronic Publication: 2023 Dec 11. |
| DOI: | 10.1242/dev.201893 |
| Abstrakt: | Toll-like receptors (TLRs) in mammalian systems are well known for their role in innate immunity. In addition, TLRs also fulfil crucial functions outside immunity, including the dorsoventral 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 junctional cytoskeletal activity. Here, we address the function of TLRs and the downstream key signal transduction component IRAK4 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 and adherens junctions, such as a loss of epithelial tension and changes in junctional actomyosin. Changes upon IRAK-4 inhibition are conserved in human bronchial epithelial cells. Knockdown 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. Competing Interests: Competing interests A.B. and K.B.S. are employees and stockholders of AstraZeneca. The authors declare no other competing interests. (© 2023. Published by The Company of Biologists Ltd.) |
| Databáze: | MEDLINE |
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