ABSTRACT
The immediate response to an invading organism is coordinated by the innate immune system. The pathogens are sensed by a family of germ line-encoded receptors recognizing conserved molecular patterns shared by large groups of pathogens. These types of ligands are often referred to as pathogen-associated molecular patterns (PAMPs) and are mainly derived from the microbial nucleic acids or cell walls. The PAMPs are recognized by members in the family of Toll-like receptors (TLRs), expressed in monocytes, macrophages, and dendritic cells. Functional TLRs are essential for our defense against microbes and initiate the inflammatory reactions. Uncontrolled TLR signaling may lead to life-threatening complications such as systemic inflammatory response syndrome (SIRS; also often referred to as septic shock), chronic inflammation, and autoimmunity. The TLR family consists of at least 10 members in humans, where they sense microbial compounds such as lipopolysaccharide (TLR4) and lipoproteins (TLR2, which dimerizes with TLR1 or TLR6), proteins (flagellin; TLR5), and viral and bacterial nucleic acids (TLR3, TLR7, TLR8, and TLR9).1,2
The different TLRs show distinct spatial distribution within the cell and, as a consequence, different trafficking patterns. TLR2 and TLR4 are expressed on the plasma membrane, on endosomes, and as a large pool in the Golgi area. TLRs 3, 7, 8, and 9 reside in the endoplasmic reticulum (ER) in unstimulated cells. In contrast
to TLR2 and TLR4, whose ligand binding and initiation of signaling occur at the plasma membrane, TLRs 3, 7, 8, and 9 are only intracellular and are mobilized from the ER to endosomes, where they bind their cognate ligands.
