Abstract
Localization of Toll-like receptors (TLR) in subcellular organelles is a major strategy to regulate innate immune responses. While TLR4, a cell-surface receptor, signals from both the plasma membrane and endosomal compartments, less is known about the functional role of endosomal trafficking upon TLR2 signaling. Here we show that the bacterial TLR2 ligands Pam3CSK4 and LTA activate NF-κB-dependent signaling from endosomal compartments in human monocytes and in a NF-κB sensitive reporter cell line, despite the expression of TLR2 at the cell surface. Further analyses indicate that TLR2-induced NF-κB activation is controlled by a clathrin/dynamin-dependent endocytosis mechanism, in which CD14 serves as an important upstream regulator. These findings establish that internalization of cell-surface TLR2 into endosomal compartments is required for NF-κB activation. These observations further demonstrate the need of endocytosis in the activation and regulation of TLR2-dependent signaling pathways.
Highlights
The innate immune system provides a first line of defense against various pathogens without the requirement of prior exposure to foreign antigens
Our results suggest that internalization of TLR2 is required to increase TNF expression in lipoteichoic acid (LTA)- and Pam3CSK4-activated monocytes
We demonstrate that TLR2, together with its co-receptors, TLR1 and TLR6, requires internalization to trigger NF-κB activation in response to LTA and Pam3CSK4, providing a novel understanding on how Toll-like receptors (TLR) coordinate ligand recognition and subsequent triggering of a specific signalization
Summary
The innate immune system provides a first line of defense against various pathogens without the requirement of prior exposure to foreign antigens. Endocytosis of plasma membrane– localized TLRs was initially thought to attenuate ligand-induced responses, but it is widely accepted that receptor internalization permits both the propagation of the signaling cascade from endosomal compartments and the generation of distinct signaling events [2,3,4]. TLR2 recognizes various ligands, and makes use of different mechanisms to provide specificity to each of them In this context, recognition by receptor heterodimerization and/or endocytosis gives rise to broader ligand specificity [3,6,7]. In addition to the TLR4 signaling that takes place at the plasma membrane through MyD88/TIRAP adaptor proteins leading to early NF-κB activation, a second signaling event was demonstrated to be initiated from the endosomal compartments through TRAM/TRIF adaptor proteins mediating late NF-κB signaling and phosphorylation of the transcription factor Interferon Regulatory Factor-3 (IRF3), which in turn regulates type I interferon (IFN) [12]. Nilsen et al have shown that a dominant negative form of Dynamin had no effect on TLR2 signaling whereas several other studies have shown that production of TNF and IL-6 is altered by inhibition of TLR2 internalization [11,15]
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