Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Microbial Physiology, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), Groningen, Netherlands.
Front Immunol. 2020 May 12;11:790. doi: 10.3389/fimmu.2020.00790. eCollection 2020.
Toll-like receptor 8 (TLR-8) plays a role in the pathogenesis of autoimmune disorders and associated gastrointestinal symptoms that reduce quality of life of patients. Dietary interventions are becoming more accepted as mean to manage onset, progression, and treatment of a broad spectrum of inflammatory conditions. In this study, we assessed the impact of -glycans derived from bovine lactoferrin (bLF) on the inhibition of TLR-8 activation. We investigated the effects of -glycans in their native form, as well as in its partially demannosylated and partially desialylated form, on HEK293 cells expressing TLR-8, and in human monocyte-derived dendritic cells (MoDCs). We found that in HEK293 cells, -glycans strongly inhibited the ssRNA40 induced TLR-8 activation but to a lesser extent the R848 induced TLR-8 activation. The impact was compared with a pharmaceutical agent, i.e., chloroquine (CQN), that is clinically applied to antagonize endosomal TLR- activation. Inhibitory effects of the -glycans were not influenced by the partially demannosylated or partially desialylated -glycans. As the difference in charge of the -glycans did not influence the inhibition capacity of TLR-8, it is possible that the inhibition mediated by the -glycans is a result of a direct interaction with the receptor rather than a result of pH changes in the endosome. The inhibition of TLR-8 in MoDCs resulted in a significant decrease of IL-6 when cells were treated with the unmodified (0.5-fold, < 0.0001), partially demannosylated (0.3-fold, < 0.0001) and partially desialylated (0.4-fold, < 0.0001) -glycans. Furthermore, the partially demannosylated and partially desialylated -glycans showed stronger inhibition of IL-6 production compared with the native -glycans. This provides evidence that glycan composition plays a role in the immunomodulatory activity of the isolated -glycans from bLF on MoDCs. Compared to CQN, the -glycans are specific inhibitors of TLR-8 activation and of IL-6 production in MoDCs. Our findings demonstrate that isolated -glycans from bLF have attenuating effects on TLR-8 induced immune activation in HEK293 cells and human MoDCs. The inhibitory capacity of -glycans isolated from bLF onTLR-8 activation may become a food-based strategy to manage autoimmune, infections or other inflammatory disorders.
Toll 样受体 8（TLR-8）在自身免疫性疾病的发病机制和相关胃肠道症状中发挥作用，这些症状降低了患者的生活质量。饮食干预作为一种管理广泛炎症疾病的发生、进展和治疗的方法，越来越被人们所接受。在这项研究中，我们评估了来源于牛乳铁蛋白（bLF）的-β-糖苷对 TLR-8 激活的抑制作用。我们研究了-β-糖苷的天然形式，以及部分去甘露糖基化和部分去唾液酸化形式，对表达 TLR-8 的 HEK293 细胞和人单核细胞衍生的树突状细胞（MoDC）的影响。我们发现，在 HEK293 细胞中，β-糖苷强烈抑制 ssRNA40 诱导的 TLR-8 激活，但对 R848 诱导的 TLR-8 激活的抑制作用较小。将其与一种临床应用于拮抗内体 TLR 激活的药物，即氯喹（CQN）进行了比较。β-糖苷的抑制作用不受部分去甘露糖基化或部分去唾液酸化的β-糖苷的影响。由于β-糖苷的电荷差异并不影响 TLR-8 的抑制能力，因此，β-糖苷介导的抑制可能是由于与受体的直接相互作用而不是内体中 pH 变化的结果。当用未修饰的（0.5 倍，<0.0001）、部分去甘露糖基化的（0.3 倍，<0.0001）和部分去唾液酸化的（0.4 倍，<0.0001）β-糖苷处理 MoDCs 时，β-糖苷在 MoDCs 中抑制 TLR-8 会导致 IL-6 的显著减少。此外，与天然β-糖苷相比，部分去甘露糖基化和部分去唾液酸化的β-糖苷对 IL-6 产生的抑制作用更强。这表明糖基组成在 bLF 来源的-β-糖苷对 MoDCs 的免疫调节活性中发挥作用。与 CQN 相比，β-糖苷是 TLR-8 激活和 MoDCs 中 IL-6 产生的特异性抑制剂。我们的研究结果表明，bLF 分离的-β-糖苷对 HEK293 细胞和人 MoDC 中 TLR-8 诱导的免疫激活具有衰减作用。bLF 分离的-β-糖苷对 TLR-8 激活的抑制能力可能成为一种基于食物的策略，用于治疗自身免疫、感染或其他炎症性疾病。
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