Activation of mammalian Toll-like receptors by endogenous agonists

Toll-like receptors activate innate and adaptive immune systems in mammals. This ancient family of receptors has been evolving since before the taxonomic split between the plant and animal kingdoms. The discovery of the mammalian Toll-like receptors was heralded as confirmation of a predicted biological system explicitly designed to detect exogenous molecules from micro-organisms. However, there is accumulating evidence that Toll-like receptors also detect endogenous agonists, such as the degradation products of macromolecules, products of proteolytic cascades, intracellular components of ruptured cells, and products of genes that are activated by inflammation. Here we review endogenous models of Toll-like receptor activation, a subject of extensive debate. Endogenous activation of mammalian Toll-like receptors may provide key insights for the treatment of multiple conditions, from atherosclerosis to transplant rejection.