ABSTRACT
Infectious and infl ammatory diseases caused by microbial pathogens, once highly prevalent only in the developing world, are now cause for global concern. The mammalian Toll-like receptors (TLRs) are one of the families of sensor receptors that recognize pathogen-associated molecular patterns (PAMPs). Not only are TLRs crucial sensors of microbial (e.g., viral, bacterial and parasitic) infections in innate immune cells, they also play important roles in the pathophysiology of infectious, infl ammatory and autoimmune diseases. Thus, the intensity and duration of TLR responses against invading microbial pathogens and endogenous danger signals must be tightly controlled. It follows that studies on the structural integrity of TLRs, their ligand interactions and signaling components may provide important information essential to our understanding of TLR-dependent immunological protection and disease intervention. Although the signaling pathways of TLR sensors are well characterized, the parameters controlling interactions between these receptors and their ligands still remain poorly defi ned. Here, we summarize the current understanding of TLR structure, function and signaling, and highlight the role of glycosylation and sialylation in TLR activation. The key interactions that induce TLR activation are identifi ed in a novel TLR-signaling platform. A mammalian neuraminidase-1 (Neu1sialidase) and matrix metalloproteinase 9 (MMP9) cross-talk in alliance with the G-protein coupled receptor (GPCR) neuromedin B is uncovered which is essential for TLR-induced receptor activation, cellular signaling and pro-infl ammatory responses.
