Endogenous ligands of TLR2 and TLR4: agonists or assistants?

The mammalian TLRs serve as key sensors of PAMPs, such as bacterial LPS, lipopeptides, and flagellins, which are present in microbial cells but not host cells. TLRs have therefore been considered to play a central role in the discrimination between "self" and "non-self". However, since the discovery of their microbial ligands, many studies have provided evidence that host-derived molecules may also stimulate TLR2- or TLR4-dependent signaling. To date, more than 20 of these endogenous TLR ligands have been proposed, which have tended to fall into the categories of released intracellular proteins, ECM components, oxidatively modified lipids, and other soluble mediators. This review aims to summarize the evidence supporting the intrinsic TLR-stimulating capacity of each of these proposed endogenous ligands with a particular emphasis on the measures taken to exclude contaminating LPS and lipopeptides from experimental systems. The emerging evidence that many of these molecules may be more accurately described as PAMP-binding molecules (PBMs) or PAMP-sensitizing molecules (PSMs), rather than genuine ligands of TLR2 or TLR4, is also summarized. The relevance of this possibility to the pathogenesis of chronic inflammatory diseases, tumor surveillance, and autoimmunity is discussed.