Endogenous toll-like receptor ligands and their biological significance

Abstract

Toll-like receptors (TLRs), a family of pattern recognition receptors, recognize and respond to conserved components of microbes and play a crucial role in both innate and adaptive immunity. In addition to binding exogenous ligands derived from pathogens, TLRs interact with endogenous molecules released from damaged tissues or dead cells and regulate many sterile inflammation processes. Putative endogenous TLR ligands include proteins and peptides, polysaccharides and proteoglycan, nucleic acids and phospholipids, which are cellular components, particularly extracellular matrix degradation products. Accumulating evidence demonstrates that endogenous ligand-mediated TLR signalling is involved in pathological conditions such as tissue injury, repair and regeneration; autoimmune diseases and tumorigenesis. The ability of TLRs to recognize endogenous stimulators appears to be essential to their function in regulating non-infectious inflammation. In this review, we summarize current knowledge of endogenous TLR ligands and discuss the biological significance of TLR signalling triggered by endogenous ligands in several sterile inflammation conditions.

Fig 1

TLR4 signalling. TLR4 engagement initiates MyD88-dependent and independent signalling pathway and leads to production of inflammatory cytokines and type I IFN. AP-1, activating protein-1; CD14, cluster of differentiation 14; IKK, IκB kinase; IRAK, IL-1R-associated kinase; IRF, IFN regulatory factor; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MD-2, myeloid differentiation protein-2; MyD88, myeloid differentiation primary-response protein 88; TAK, TGF-β activated kinase; TBK, TANK binding kinase; TIRAP, Toll/interleukin-1 receptor domain-containing adaptor protein; TLR, toll-like receptor; TRAF, tumour necrosis factor receptor-associated factor; TRAM, TRIF-related adaptor molecule; TRIF, TIR-domain-containing adaptor inducing IFN-β; NF-κB, nuclear factor kappa B.

Fig 2

A proposed mechanism of inflammatory response in ischemia/reperfusion injury. Ischemia/reperfusion injury results in release of endogenous TLR ligands such as HMGB1, HSP and hyaluronan. Endogenous molecules bind to TLRs on DCs, macrophages and neutrophils that are recruited or infiltrated to injury sites and induce production of cytokines and chemokines and an inflammatory response.