The Toll-like receptors and their role in septic shock

The Toll-like receptors (TLRs) are a class of pattern recognition molecules with unique functions in the innate and the acquired immune systems. The innate immune response has evolved as the immediate host defence system in response to foreign structures and it also serves to prime the adaptive immune response. As such, the TLRs set the tone and pace of the inflammatory response that follows initial contact with a microbial pathogen over the course of the following minutes, hours and days. Sepsis, a leading cause of death in critically ill patients worldwide, is defined as 'the systemic inflammatory response syndrome that occurs during infection' [1]; that is, sepsis is the orchestration of the events controlled by the gene products triggered by signals transduced through the TLRs. Through analysis of the human genome, ten TLRs have been identified, and several of them have been characterised with respect to their associated ligands. Following engagement of the cognate ligand to the ectodomain of each TLR, the assembly of intracellular homo- or heterodimers or multimers induces cell signalling. The receptors are variably expressed on different types of cells, such as neutrophils, dendritic cells, lymphocytes, endothelial cells etc. and can be up- and downregulated, blocked or triggered by mimetic substances. By controlling or modifying TLR responses, the trajectory of the entire septic process may be modified. This review covers the events responsible for TLR activation in detail, with an emphasis on possible points of pharmacological intervention.