Weak Agonistic LPS Restores Intestinal Immune Homeostasis
Weak Agonistic LPS Restores Intestinal Immune Homeostasis
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DOI：
10.1016/j.ymthe.2019.07.007
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发表时间：
2019-07
影响因子：
12.4
通讯作者：
Alex Steimle;Lena Michaelis;F. Di Lorenzo;T. Kliem;Tobias Münzner;J. Maerz;A. Schäfer;Anna Lange;R. Parusel;K. Gronbach;K. Fuchs;A. Silipo;H. Öz;B. Pichler;I. Autenrieth;A. Molinaro;J. Frick
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作者：
Alex Steimle;Lena Michaelis;F. Di Lorenzo;T. Kliem;Tobias Münzner;J. Maerz;A. Schäfer;Anna Lange;R. Parusel;K. Gronbach;K. Fuchs;A. Silipo;H. Öz;B. Pichler;I. Autenrieth;A. Molinaro;J. Frick
脂多糖（lps）由革兰氏阴性菌产生，是存在于肠腔中最丰富和最有效的免疫调节物质之一。激动性LPS与宿主骨髓分化-2/ toll样受体4 （MD-2/TLR4）受体复合物的相互作用导致核因子κB （NF-κB）活化，随后强烈诱导促炎免疫反应。在这里，我们从一种常见的肠道共生菌，普通拟杆菌（BVMPK）中分离出LPS，它只提供弱的激动活性。这种弱激动活性导致实验性结肠炎小鼠模型中炎症免疫反应的改善，与强激动剂和拮抗剂形成鲜明对比。在这种情况下，BVMPK LPS给药严重肠道炎症小鼠，仅在2周内就重新建立了肠道免疫稳态，导致所有炎症症状清除。弱激动性LPS的这些消炎特性是基于在肠固有层CD11c+细胞中通过MD-2/TLR4受体复合物轴诱导一种特殊类型的内毒素耐受性。因此，弱激动性LPS是治疗肠道免疫系统病理性过度激活疾病的一种有希望的药物，例如炎症性肠病。
Generated by gram-negative bacteria, lipopolysaccharides (LPSs) are one of the most abundant and potent immunomodulatory substances present in the intestinal lumen. Interaction of agonistic LPS with the host myeloid-differentiation-2/Toll-like receptor 4 (MD-2/TLR4) receptor complex results in nuclear factor κB (NF-κB) activation, followed by the robust induction of pro-inflammatory immune responses. Here we have isolated LPS from a common gut commensal,Bacteroides vulgatusmpk (BVMPK), which provides only weak agonistic activity. This weak agonistic activity leads to the amelioration of inflammatory immune responses in a mouse model for experimental colitis, and it was in sharp contrast to strong agonists and antagonists. In this context, the administration of BVMPK LPS into mice with severe intestinal inflammation re-established intestinal immune homeostasis within only 2 weeks, resulting in the clearance of all symptoms of inflammation. These inflammation-reducing properties of weak agonistic LPS are grounded in the induction of a special type of endotoxin tolerance via the MD-2/TLR4 receptor complex axis in intestinal lamina propria CD11c+cells. Thus, weak agonistic LPS represents a promising agent to treat diseases involving pathological overactivation of the intestinal immune system, e.g., in inflammatory bowel diseases.