Suppression of Toll-like receptor-mediated innate immune responses at the ocular surface by the membrane-associated mucins MUC1 and MUC16.
Suppression of Toll-like receptor-mediated innate immune responses at the ocular surface by the membrane-associated mucins MUC1 and MUC16.
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在眼表上皮上表达的膜相关粘蛋白（MAM）形成致密的糖萼，其被假设为保护角膜和结膜免受外部损伤。在这项研究中，MAMs MUC 1和MUC 16，在角膜上皮的顶端表面上表达，抑制Toll样受体（TLR）介导的先天性免疫反应的假设进行了测试。使用培养以表达MAMs的角膜上皮细胞的体外模型，我们表明MUC 1或MUC 16的表达减少与细胞暴露于TLR 2和TLR 5激动剂、热灭活单核细胞增生李斯特菌和鞭毛蛋白后促炎细胞因子IL-6、IL-8和TNF-α的信息和分泌蛋白水平增加相关。由于小鼠在角膜上皮中表达MUC 1（但不表达MUC 16），因此使用Muc 1-/-小鼠模型来扩展体外发现。事实上，与野生型小鼠相比，在将摘除的眼睛暴露于TLR 2和TLR 5激动剂后，Muc 1-/-小鼠角膜上皮中的IL-6和TNF-α信使水平增加。我们的研究结果表明，MAMs MUC 1和MUC 16有助于通过限制TLR介导的先天性免疫应答来维持眼表的免疫稳态。
Membrane-associated mucins (MAMs) expressed on the ocular surface epithelium form a dense glycocalyx, which is hypothesized to protect the cornea and conjunctiva from external insult. In this study, the hypothesis that the MAMs MUC1 and MUC16, expressed on the apical surface of the corneal epithelium, suppress Toll-like receptor (TLR)-mediated innate immune responses was tested. Using an in vitro model of corneal epithelial cells that are cultured to express MAMs, we show that reduced expression of either MUC1 or MUC16 correlates with increased message and secreted protein levels of the proinflammatory cytokines IL-6, IL-8, and TNF-α following exposure of cells to the TLR2 and TLR5 agonists, heat killed Listeria monocytogenes and flagellin, respectively. Since mice express MUC1 (but not MUC16) in the corneal epithelium, a Muc1-/- mouse model was used to extend in vitro findings. Indeed, IL-6 and TNF-α message levels were increased in the corneal epithelium of Muc1-/- mice, in comparison to wild type mice, following exposure of enucleated eyes to the TLR2 and TLR5 agonists. Our results suggest that the MAMs MUC1 and MUC16 contribute to the maintenance of immune homeostasis at the ocular surface by limiting TLR-mediated innate immune responses.
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