MRC-Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
Oncology R&D, Precision Medicine and Biosamples, R&D, AstraZeneca, Pepparedsleden 1, Nova, Mölndal, SE-431 83, Sweden.
Development. 2023 Dec 15;150(24). doi: 10.1242/dev.201893. Epub 2023 Dec 11.
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.
哺乳动物系统中的 Toll 样受体 (TLRs) 以其在先天免疫中的作用而闻名。此外，TLRs 在免疫以外的领域也发挥着至关重要的作用，包括果蝇原始 Toll 受体的背腹模式形成功能和小鼠的神经发生。最近在果蝇中的发现表明 TLRs 在上皮细胞中的连接细胞骨架活性模式形成中起关键作用。在这里，我们研究了 TLRs 及其下游关键信号转导成分 IRAK4 在人上皮细胞中的功能。我们使用分化的人 Caco-2 细胞作为肠道上皮的模型，表明这些细胞表现出基础 TLR 信号，如 p-IRAK4 所示，并且阻断 IRAK4 功能会导致上皮紧密性丧失，涉及紧密连接和黏附连接的关键变化，例如上皮张力丧失和连接肌动球蛋白的变化。IRAK-4 抑制后的变化在人支气管上皮细胞中是保守的。IRAK4 和某些 TLRs 的敲低模拟了抑制剂处理。这些数据表明了一种模型，即上皮连接附近的 TLR 受体可能参与上皮状态的连续感知，以促进上皮紧密性和完整性。
