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A novel synthetic lipopeptide is allergy-protective by the induction of LPS-tolerance

机译：新型合成脂肽通过诱导LPS耐受而具有抗过敏作用

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Background: Exposure to the environment of traditional farms can protect children from some allergic disease. Due to this exposure, TLR2 expression in these children is increased. TLR2 ligands derived from gram-positive bacteria are found in the dust of these farms. Objectives: We proved whether a synthetic lipopeptide binding to the TLR1/2 heterodimer is able to protect from allergic disease in two different murine models of allergy. We also investigated the immunological mechanisms underlying the protective properties of the lipopeptide. Methods: We synthesized a lipopeptide derived from a germination lipoprotein of Bacillus cereus (LPGerD). We evaluated the immunomodulatory activity of LPGerD in a murine model of systemic sensitization (OVA/Alum) and in a model in which mice were sensitized with OVA pulsed bone-marrow-derived dendritic cells (BMDCs) via the airways. Furthermore, the induction of LPS tolerance was studied. Results: Treatment of mice with LPGerD in a mouse model of asthma led to protection against sensitization and airway inflammation. Similarly, bone-marrow-derived dendritic cells (BMDCs) pre-treated with LPGerD were not able to prime mice for allergic immune response. We observed that pre-treatment with LPGerD led to the induction of a LPS-tolerant state in BMDCs. These cells secreted markedly lower amounts of pro-inflammatory cytokines upon LPS stimulation. Furthermore, we observed an up-regulation of IRAK-M mRNA in BMDCs pre-treated with LPGerD. Conclusions and Clinical Relevance: Our results suggest that induction of a LPS-tolerant state in antigen-presenting cells (APCs) may contribute to the protective effect of a farming environment. TLR2 agonists similar to those appearing in cowshed dust extracts, such as our synthetic LPGerD, lead to the ignorance of the LPS stimulus, which is important for the activation of APCs to mount a Th2 immune response. This substance might be a promising candidate for allergy-preventive treatments as LPGerD had only low pro-inflammatory characteristics.
机译：背景：暴露于传统农场的环境可以保护儿童免受某些过敏性疾病的侵害。由于这种接触，这些孩子中TLR2的表达增加。在这些农场的尘土中发现了来自革兰氏阳性细菌的TLR2配体。目的：我们证明了在两种不同的鼠类过敏模型中，合成的脂肽与TLR1 / 2异源二聚体的结合是否能够预防过敏性疾病。我们还研究了脂肽保护特性的免疫机制。方法：我们合成了蜡状芽孢杆菌（Laccer cereus）发芽脂蛋白（LPGerD）衍生的脂肽。我们在系统性敏化的小鼠模型（OVA / Alum）中以及在小鼠通过气道用OVA脉冲骨髓衍生树突状细胞（BMDC）致敏的模型中评估了LPGerD的免疫调节活性。此外，研究了LPS耐受性的诱导。结果：在哮喘小鼠模型中用LPGerD小鼠治疗可预防敏化和气道炎症。同样，用LPGerD预处理的骨髓来源树突状细胞（BMDC）无法引发小鼠过敏性免疫反应。我们观察到，LPGerD预处理导致BMDC中LPS耐受状态的诱导。在LPS刺激下，这些细胞分泌的促炎细胞因子的数量明显减少。此外，我们观察到用LPGerD预处理的BMDC中IRAK-M mRNA的上调。结论与临床意义：我们的结果表明，在抗原呈递细胞（APC）中诱导出LPS耐受状态可能有助于农业环境的保护作用。 TLR2激动剂类似于牛场粉尘提取物中的激动剂，例如我们的合成LPGerD，会导致对LPS刺激的无知，这对于激活APC进行Th2免疫反应至关重要。该物质可能是抗过敏治疗的有希望的候选物，因为LPGerD仅具有低促炎特性。

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