Immune Sensing of Cell Death through Recognition of Histone Sequences by C-Type Lectin-Receptor-2d Causes Inflammation and Tissue Injury
Immune Sensing of Cell Death through Recognition of Histone Sequences by C-Type Lectin-Receptor-2d Causes Inflammation and Tissue Injury
复制标题
DOI：
10.1016/j.immuni.2019.11.013
复制
发表时间：
2020-01-14
期刊：
影响因子：
32.4
通讯作者：
Rock, Kenneth L.
中科院分区：
文献类型：
--
作者：
Lai, Jiann-Jyh;Cruz, Freidrich M.;Rock, Kenneth L.
免疫系统监测细胞的健康状况，并受到坏死的刺激。在这里，我们研究了驱动这种反应的受体和配体。在C型凝集素受体的靶向筛选中，一名Clec2d记者对坏死细胞的裂解产物做出了反应。生化纯化鉴定出组蛋白是Clec2d配体，它是游离的和与核小体或中性粒细胞胞外陷阱结合的。Clec2d识别组蛋白尾部的多碱基序列，这种识别对这些序列的翻译后修饰很敏感。与WT小鼠相比，Clec2d(-/-)小鼠对注射的组蛋白的促炎反应减少，组织损伤较少，在肝毒性损伤模型中提高了存活率。在巨噬细胞中，Clec2d定位于质膜和内小体。组蛋白与Clec2d结合不能刺激激酶激活或细胞因子的产生。相反，组蛋白结合的DNA以Clec2d依赖的方式刺激内体TLR9依赖的反应。因此，Clec2d与坏死性细胞死亡时释放的组蛋白结合，导致炎症和组织损伤。
The immune system monitors the health of cells and is stimulated by necrosis. Here we examined the receptors and ligands driving this response. In a targeted screen of C-type lectin receptors, a Clec2d reporter responded to lysates from necrotic cells. Biochemical purification identified histones, both free and bound to nucleosomes or neutrophil extracellular traps, as Clec2d ligands. Clec2d recognized poly-basic sequences in histone tails and this recognition was sensitive to post-translational modifications of these sequences. As compared with WT mice, Clec2d(-/-) mice exhibited reduced proinflammatory responses to injected histones, and less tissue damage and improved survival in a hepatotoxic injury model. In macrophages, Clec2d localized to the plasma membrane and endosomes. Histone binding to Clec2d did not stimulate kinase activation or cytokine production. Rather, histone-bound DNA stimulated endosomal Tlr9-dependent responses in a Clec2d-dependent manner. Thus, Clec2d binds to histones released upon necrotic cell death, with functional consequences to inflammation and tissue damage.