Toll-like receptors as targets in chronic liver diseases

Abstract

Toll-like receptors (TLRs) recognize pathogen associated molecular patterns (PAMPs) to detect the presence of pathogens. In addition to their role in innate immunity, TLRs also play a major role in the regulation of inflammation, even under sterile conditions such as injury and wound healing. This involvement has been suggested to be depend, at least in part, on the ability of TLRs to recognize several endogenous TLR ligands termed damage associated molecular patterns (DAMPs). The liver not only represents a major target of bacterial PAMPs in many disease states but also upregulates several DAMPs following injury. Accordingly, TLR-mediated signals have been implicated in a number of chronic liver diseases. Here, we will summarize recent findings on the role TLRs and TLR ligands in the pathophysiology of liver fibrosis and cirrhosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease and hepatocellular carcinoma, and highlight the potential role of TLR agonists, antagonists and probiotics for the treatment of chronic liver disease.

Core circadian protein CLOCK is a positive regulator of NF-κB–mediated transcription

“…To test whether daily variations in susceptibility to inflammatory challenge correlates with NF-κB activation, we first compared the acute response of BALB/c mice to the TLR4 agonist LPS administered at two time points: at the middle of the light period of the daily cycle at Zeitgeber time ZT6 (in Zeitgeber time, ZT0 corresponds to the beginning of the lights-on period of the daily cycle) or at the middle of the dark period (ZT18). Systemic administration of LPS is highly toxic because the strong induction of proinflammatory cytokines results in septic shock (14). Consistent with previous reports, mice challenged at ZT18 (during the active phase in nocturnal animals) tolerated LPS-induced acute inflammation much better than mice challenged in the middle of their rest period (ZT6) (Fig.…”

Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors

“…Here we identified TLR9 and STING to be critically involved as sensors of free genomic dsDNA released during cell death. 31 The importance of TLR9 for the sensing of DNA from apoptotic hepatocytes and subsequent liver damage was already shown by Watanabe et al 32 In line with this, STING-IRF3 signaling has recently been implied in alcoholic liver disease and STING deficiency prevented interferon regulatory transcription factor (IRF) 3-mediated mitochondrial hepatocellular apoptosis. 33 In this context, cytosolic dsDNA, which activates STING via cGMP-AMP synthase (cGAS), has been suggested to be crucial for cell death in vitro.…”

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

“…TLR-mediated signals are transduced via 2 major signaling pathways dependent or independent of the Myeloid differentiation primary response protein (88) (MyD88). 58 MyD88 is an essential part of the signaling cascade for all TLRs except for TLR 3, which induces MyD88-independent signaling through a TRIF-mediated pathway. 55 …”