Abstract
Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies.
Highlights
Toll-like receptors (TLRs) are evolutionarily conserved trans-membrane proteins originally identified in mammals on the basis of their homology with Toll, a Drosophila receptor that contributes to development in the embryo, and in the production of antimicrobial peptides against microorganism invasion in the adult fly [1,2]
We introduce TLR signal transduction and the functional role of TLR4 signaling in liver injury
HSP70 can induce tumor necrosis factor (TNF)-a production by human monocytes, which is inhibited by anti-TLR4 [49]. These findings suggest that HSP60 and HSP70 are endogenous ligands of the TLR4 complex, and that there is a role for TLRs in innate immune discrimination of normal versus stressed or damaged tissue cells
Summary
Toll-like receptors (TLRs) are evolutionarily conserved trans-membrane proteins originally identified in mammals on the basis of their homology with Toll, a Drosophila receptor that contributes to development in the embryo, and in the production of antimicrobial peptides against microorganism invasion in the adult fly [1,2]. Drug-induced liver diseases TLR4 is involved in the generation of steatosis, congestion and necrosis from paracetamol (acetaminophen; APAP) [89] through release of inflammatory cytokines (TNF-a), induction of iNOS and peroxynitrite, and depletion of glutathione These events occur in response to LPS and possibly endogenous ligands released from the ECM during chemical or mechanical injury. Such injuries can further amplify systemic inflammatory immune responses by enhancing TLR4 reactivity, and Figure 2 Activation of the Toll-like receptor (TLR) signaling in liver injuries. Activation of TLR4 by both pathogen-associated molecular patterns (PAMPs; exogenous ligands, for example, lipopolysaccharide (LPS)) and damage-associated molecular patterns (DAMPs; endogenous ligands, for example, high mobility group box (HMGB)1) induces pre-inflammatory cytokines and chemokines, thereby enhancing liver inflammation, injury and fibrogenesis. Increasing evidence suggests that immune modulators such as TLR4 ligands or agonists could be successfully used as therapeutic agents in infectious liver diseases, such as HBV and HCV [93,156]
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