The fungal ligand chitin directly binds TLR2 and triggers inflammation dependent on oligomer size
The fungal ligand chitin directly binds TLR2 and triggers inflammation dependent on oligomer size
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DOI：
10.15252/embr.201846065
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发表时间：
2018-12-01
期刊：
影响因子：
7.7
通讯作者：
Weber, Alexander N. R.
中科院分区：
文献类型：
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作者：
Fuchs, Katharina;Gloria, Yamel Cardona;Weber, Alexander N. R.
甲壳素是自然界中含量第二丰富的多糖，与真菌感染和哮喘有关。然而，由于使用了纯度和分子组成未知的聚合粗制甲壳素，因此直接与甲壳素结合并发出免疫激活和炎症信号的真正免疫受体尚未被明确识别。通过使用已定义的甲壳素(N-乙酰-氨基葡萄糖)低聚物，我们发现6个亚单位长的甲壳质链是最小的免疫活性基序，天然免疫受体Toll样受体(TLR2)是人类和小鼠免疫细胞上的主要真菌甲壳素传感器。几丁质低聚物直接与TLR2结合具有纳摩尔亲和力，与已知的分枝杆菌TLR2配体相比，这种真菌TLR2配体显示出重叠和不同的信号结果。出乎意料的是，由五个或更少亚基组成的甲壳素低聚物不活跃，这暗示着一种大小依赖的免疫调节系统，似乎在植物和人类中是保守的。由于阻断甲壳素-TLR2的相互作用在体外和体内有效地防止了甲壳素介导的炎症，我们的研究强调了甲壳素-TLR2的相互作用是开发甲壳素相关病理和真菌疾病新疗法的潜在靶点。
Chitin is the second most abundant polysaccharide in nature and linked to fungal infection and asthma. However, bona fide immune receptors directly binding chitin and signaling immune activation and inflammation have not been clearly identified because polymeric crude chitin with unknown purity and molecular composition has been used. By using defined chitin (N-acetyl-glucosamine) oligomers, we here identify six-subunit-long chitin chains as the smallest immunologically active motif and the innate immune receptor Toll-like receptor (TLR2) as a primary fungal chitin sensor on human and murine immune cells. Chitin oligomers directly bind TLR2 with nanomolar affinity, and this fungal TLR2 ligand shows overlapping and distinct signaling outcomes compared to known mycobacterial TLR2 ligands. Unexpectedly, chitin oligomers composed of five or less subunits are inactive, hinting to a size-dependent system of immuno-modulation that appears conserved in plants and humans. Since blocking of the chitin-TLR2 interaction effectively prevents chitin-mediated inflammation in vitro and in vivo, our study highlights the chitin-TLR2 interaction as a potential target for developing novel therapies in chitin-related pathologies and fungal disease.