Ivanov Stanimir, Dragoi Ana-Maria, Wang Xin, Dallacosta Corrado, Louten Jennifer, Musco Giovanna, Sitia Giovanni, Yap George S, Wan Yinsheng, Biron Christine A, Bianchi Marco E, Wang Haichao, Chu Wen-Ming
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
Blood. 2007 Sep 15;110(6):1970-81. doi: 10.1182/blood-2006-09-044776. Epub 2007 Jun 4.
CpG-DNA or its synthetic analog CpG-ODN activates innate immunity through Toll-like receptor 9 (TLR9). However, the mechanism of TLR9 activation by CpG-DNA remains elusive. Here we have identified HMGB1 as a CpG-ODN-binding protein. HMGB1 interacts and preassociates with TLR9 in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), and hastens TLR9's redistribution to early endosomes in response to CpG-ODN. CpG-ODN stimulates macrophages and dendritic cells to secrete HMGB1; in turn, extracellular HMGB1 accelerates the delivery of CpG-ODNs to its receptor, leading to a TLR9-dependent augmentation of IL-6, IL-12, and TNFalpha secretion. Loss of HMGB1 leads to a defect in the IL-6, IL-12, TNFalpha, and iNOS response to CpG-ODN. However, lack of intracellular TLR9-associated HMGB1 can be compensated by extracellular HMGB1. Thus, the DNA-binding protein HMGB1 shuttles in and out of immune cells and regulates inflammatory responses to CpG-DNA.
CpG-DNA或其合成类似物CpG-ODN通过Toll样受体9（TLR9）激活先天免疫。然而，CpG-DNA激活TLR9的机制仍不清楚。在此，我们鉴定出高迁移率族蛋白B1（HMGB1）为一种CpG-ODN结合蛋白。HMGB1在内质网-高尔基体中间区室（ERGIC）中与TLR9相互作用并预先结合，并促使TLR9响应CpG-ODN重新分布到早期内体。CpG-ODN刺激巨噬细胞和树突状细胞分泌HMGB1；反过来，细胞外HMGB1加速CpG-ODN向其受体的传递，导致IL-6、IL-12和肿瘤坏死因子α（TNFα）分泌的TLR9依赖性增强。HMGB1的缺失导致对CpG-ODN的IL-6、IL-12、TNFα和诱导型一氧化氮合酶（iNOS）反应缺陷。然而，细胞内与TLR9相关的HMGB1的缺乏可由细胞外HMGB1补偿。因此，DNA结合蛋白HMGB1在免疫细胞内外穿梭并调节对CpG-DNA的炎症反应。
