Ling Guang Sheng, Bennett Jason, Woollard Kevin J, Szajna Marta, Fossati-Jimack Liliane, Taylor Philip R, Scott Diane, Franzoso Guido, Cook H Terence, Botto Marina
Centre for Complement and Inflammation Research, Department of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Nat Commun. 2014;5:3039. doi: 10.1038/ncomms4039.
Tuned and distinct responses of macrophages and dendritic cells to Toll-like receptor 4 (TLR4) activation induced by lipopolysaccharide (LPS) underpin the balance between innate and adaptive immunity. However, the molecule(s) that confer these cell-type-specific LPS-induced effects remain poorly understood. Here we report that the integrin α(M) (CD11b) positively regulates LPS-induced signalling pathways selectively in myeloid dendritic cells but not in macrophages. In dendritic cells, which express lower levels of CD14 and TLR4 than macrophages, CD11b promotes MyD88-dependent and MyD88-independent signalling pathways. In particular, in dendritic cells CD11b facilitates LPS-induced TLR4 endocytosis and is required for the subsequent signalling in the endosomes. Consistent with this, CD11b deficiency dampens dendritic cell-mediated TLR4-triggered responses in vivo leading to impaired T-cell activation. Thus, by modulating the trafficking and signalling functions of TLR4 in a cell-type-specific manner CD11b fine tunes the balance between adaptive and innate immune responses initiated by LPS.
巨噬细胞和树突状细胞对脂多糖（LPS）诱导的Toll样受体4（TLR4）激活的特异性反应，是固有免疫和适应性免疫平衡的基础。然而，赋予这些细胞类型特异性LPS诱导效应的分子仍知之甚少。在此，我们报道整合素α(M)（CD11b）仅在髓样树突状细胞中而非巨噬细胞中，对LPS诱导的信号通路起正向调节作用。在树突状细胞中，其CD14和TLR4的表达水平低于巨噬细胞，CD11b可促进依赖髓样分化因子88（MyD88）和不依赖MyD88的信号通路。特别地，在树突状细胞中，CD11b促进LPS诱导的TLR4内吞作用，并且是随后在内体中进行信号传导所必需的。与此一致，CD11b缺陷会减弱树突状细胞介导的体内TLR4触发反应，导致T细胞激活受损。因此，CD11b通过以细胞类型特异性方式调节TLR4的运输和信号功能，精细调节了LPS引发的适应性免疫和固有免疫反应之间的平衡。
