Toll-Like Receptor Signaling in Liver Diseases

Toll-like receptors (TLRs) constitute a family of pattern recognition receptors that detect microbial and damage-associated molecular patterns, orchestrating innate immune responses within the liver. Expressed on Kupffer cells, hepatocytes, hepatic stellate cells (HSCs) and endothelial populations, TLR activation engages adaptor molecules such as MyD88 or TRIF, triggering NF-κB, MAPK and IRF pathways. In acute injury, this response facilitates pathogen clearance and tissue repair, but persistent or excessive TLR signalling drives chronic inflammation, HSC activation and extracellular matrix deposition, culminating in fibrosis. TLR4 has emerged as a central mediator of fibrogenic signalling, linking gut-derived lipopolysaccharide to HSC activation, while other family members (including TLR2, TLR3 and TLR9) contribute to steatohepatitis, viral hepatitis and alcoholic liver disease. Crosstalk between TLR pathways and metabolic regulators underscores the interface between immunity and lipid homeostasis, with implications for non-alcoholic fatty liver disease. Therapeutic strategies that modulate TLR signalling—ranging from receptor antagonists to microRNA mimetics—offer promise in restraining inflammatory cascades, attenuating fibrosis and restoring hepatic function.

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Toll-Like Receptor Signaling in Liver Diseases publication trend

The graph below shows the total number of articles in toll-like receptor signaling in liver diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Toll-like receptor (TLR): A class of innate immune receptors that recognise microbial components and initiate inflammatory signalling.

MyD88: An adaptor protein critical for most TLR signalling pathways, leading to downstream activation of NF-κB and MAP kinases.

Hepatic stellate cell (HSC): A liver-resident cell that, when activated, secretes extracellular matrix proteins and drives fibrosis.

Kupffer cell: A specialised liver macrophage involved in clearance of pathogens and regulation of inflammation.

Pathogen-associated molecular pattern (PAMP): Conserved molecular motifs on microbes recognised by TLRs to trigger immune responses.

References

1. Toll‐Like Receptor Signaling and Liver Fibrosis. Gastroenterology Research and Practice (2010).
2. MicroRNA-146a-5p attenuates irradiation-induced and LPS-induced hepatic stellate cell activation and hepatocyte apoptosis through inhibition of TLR4 pathway. Cell Death & Disease (2018).
3. MyD88 in hepatic stellate cells enhances liver fibrosis via promoting macrophage M1 polarization. Cell Death & Disease (2022).
4. MyD88 in Macrophages Enhances Liver Fibrosis by Activation of NLRP3 Inflammasome in HSCs. International Journal of Molecular Sciences (2021).