Host survival requires defense mechanisms against external danger substances, including the ability to discriminate “nonself” from “self” and to eliminate or neutralize danger molecules. The mechanisms by which the immune system detects diverse danger signals were only recently elucidated with the discovery of Toll-like receptors (TLRs). TLRs are pattern recognition receptors (PRRs) on the cell-surface of immune cells, characterized by extracellular leucine-rich repeats (LRRs) and an intracellular Toll/IL-1 receptor (TIR) domain (Fig 1). TLRs recognize invariant molecular structures called pathogen-associated molecular patterns (PAMPs) (Schroder and Tschopp, 2010; Tschopp et al., 2003). As a result, there is release of pro-inflammatory “alarm” cytokines, including IL-1β, one of the most potent endogenous pyrogens, as well as tumor necrosis factor-alpha (TNFα) and IL-6 (Tschopp et al., 2003).
