Tolls: You Pay Them on the Way In and on the Way Out!

Toll-like receptors (TLRs) are important components of the innate immune system, the evolutionary ancient response system consisting of pattern recognition proteins that recognize pathogen associated molecular patterns (PAMPs). TLRs are a series (10 in humans) of cell surface or intracellular receptor proteins that contain signaling motifs that are structurally similar to the mammalian interleukin (IL)-1 receptor and the Toll protein of insects. In mammals, TLRs function by recognizing viruses, bacteria, fungi, and parasites on the basis of their PAMPs, and then activating cells to produce cytokines including interferon (IFN) and inflammatory cytokines such as IL-1 and tumor necrosis factor that may either lead to local or systemic inflammation (reviewed in [1]). TLRs also activate the adaptive immune responses (B and T cells). As a result, they are critical to the initial host response to infection. TLR4 was originally described as the cell surface receptor that signaled the binding of lipopolysaccharide and was therefore responsible for septic shock after infection with gram-negative organisms. TLR2 was initially shown to be important in the sepsis syndrome caused by gram-positive organisms.