CD14 Controls the LPS-Induced Endocytosis of Toll-like Receptor 4

The transport of Toll-like Receptors (TLRs) to various organelles has emerged as an essential means by which innate immunity is regulated. While most of our knowledge is restricted to regulators that promote the transport of newly synthesized receptors, the regulators that control TLR transport after microbial detection remain unknown. Here, we report that the plasma membrane localized Pattern Recognition Receptor (PRR) CD14 is required for the microbe-induced endocytosis of TLR4. In dendritic cells, this CD14-dependent endocytosis pathway is upregulated upon exposure to inflammatory mediators. We identify the tyrosine kinase Syk and its downstream effector PLCγ2 as important regulators of TLR4 endocytosis and signaling. These data establish that upon microbial detection, an upstream PRR (CD14) controls the trafficking and signaling functions of a downstream PRR (TLR4). This innate immune trafficking cascade illustrates how pathogen detection systems operate to induce both membrane transport and signal transduction. [Display omitted] ► CD14 is a receptor for LPS that promotes TLR4 endocytosis and interferon expression ► CD14-induced endocytosis occurs independently of TLR4 signaling ► CD14-induced endocytosis is an ITAM-mediated process dependent on Syk and PLCg2 ► Mature dendritic cells exhibit enhanced CD14-dependent responses to bacteria The pattern recognition receptor CD14 not only delivers bacterial lipopolysaccharide to TLR4 on the plasma membrane of dendritic cells but also regulates TLR4 endocytosis and trafficking to the endosomes to trigger interferon production.