Toll-Like Receptor Signaling and Its Inducible Proteins

Various cell types, including macrophages, dendritic cells (DCs), neutrophils, natural killer cells, and fibroblasts, express Toll-like receptors (TLRs) that activate the immune system (1, 2). TLRs are type I transmembrane proteins with ectodomains containing leucine-rich repeats that mediate the recognition of pathogen-associated molecular patterns (PAMPs) derived from pathogens, and damage-associated molecular patterns (DAMPs) from dying or injured cells. TLRs harbor transmembrane domains and intracellular Toll–interleukin-1 (IL-1) receptor (TIR) domains in addition to leucine-rich repeat domains, and some adaptor molecules bind to them to activate the downstream signaling pathways. Various organisms express the TLR family, especially mammals, and 13 types of TLRs have been reported. TLR1 to -9 are conserved in both the mouse and human. However, in mice, a retroviral insertion has rendered the TLR10 molecule nonfunctional. TLR11, -12, and -13 do not occur in humans. The active TLRs localize differently. TLR1, -2, -4, -5, -6, and -10 are expressed on the cell surface, whereas TLR3, -7, -8, -9, -11, -12, and -13 are expressed in the endosome (3 , 4). Studies of mice deficient in each TLR have shown that each TLR has a distinct function in terms of PAMP recognition and the immune responses.