Toll-like receptors in pathophysiology of liver diseases

Table 1 Toll-like receptor expression and their signaling in the liver[5,9,11,15,23,33,49]

TLR subfamily	Members	Expression of cell population in the liver (protein level)	Location	Ligand (origin)	Signaling	Final product-effect
TLR2 subfamily	TLR1/2	NK cells, DCs (h)	Plasma membrane	Bacterial lipoproteins Triacylated lipopeptides	TIRAP-MyD88-NF-κB/AP-1/IRF5 pathway	Pro- and anti-inflammatory cytokines excluding type 1 IFNs; the apoptotic cascade via recruiting FADD leading to caspase-8 activation
	TLR2/6	Hepatocytes, Kupffer cells, NK cells, B cells, activated T cells, DCs (m), biliary epithelial cells		Diacylated lipopeptides LPS of Gram-positive bacteria Fungal zymosan Mycoplasma lipopeptides	TIRAP-MyD88-NF-κB/AP-1 pathway
	TLR10	Unknown		ND
TLR3 subfamily	TLR3	Hepatocytes, LSECs, Kupffer cells, NK cells, NKT cells, activated T cells, cDCs (m), biliary epithelial cells	Endosome	Double-stranded RNA (viruses)	PI3K/TRIF-IRF3 pathway TRAM-TRIF-NF-κB pathway PI3K/TRIF-RIP1-NF-κB pathway	Production of type 1 IFNs; the apoptotic cascade via recruiting FADD leading to caspase 8 activation; DC maturation
TLR4 subfamily	TLR41	Hepatocytes, LSECs, Kupffer cells, NK cells, B cells, activated T cells, DCs (m), biliary epithelial cells, HSCs	Plasma membrane	LPS of Gram-negative bacteria; fusion protein (respiratory syncytial virus), envelope protein (mouse mammary-tumor virus); HMGB1, hyaluronan, HSP60, free fatty acids (endogenous ligands); HSP72 (cells during stress and injury) surfactant protein A; fibrinogen; fibronectin extra domain A	TIRAP-MyD88-NF-κB/AP-1 pathway TRAM-TRIF-NF-κB/IRF3 pathway	Pro- and anti-inflammatory cytokines excluding type 1 IFNs; the apoptotic cascade via recruiting FADD leading to caspase 8 activation; DC maturation; activating caspase-1 through adaptor molecule apoptosis associated speck-like protein2
TLR5 subfamily	TLR5	Biliary epithelial cells	Plasma membrane	Flagellin protein (bacteria)	MyD88-NF-κB/IRF5 pathway	Pro- and anti-inflammatory cytokines excluding type 1 IFNs
TLR9 subfamily	TLR7/8	NK cells, B cells, DCs (h), DCs (m)	Endosome	Single-stranded RNA (viruses), double-stranded, shortinterfering RNA (siRNA)	MyD88 and endosomal acidification (maturation)-IRF7 pathway; MyD88- NF-κB pathway	High levels of type 1 IFN production in pDCs; proinflammatory cytokine production
	TLR9	LSECs, Kupffer cells, NK cells, B in mDCs and macrophages		Imidazoquinoline CpG-containing viral or bacterial DNA Endogenous host-DNA

¹TLR4 requires LPS-binding protein (LBP), CD14 and MD2 to recognize LPS;

²Containing a caspase recruitment domain (ASC)[33]. RIP1: Receptor-interacting protein 1; FADD: Fas-associated death domain; TLR: Toll-like receptors; LPS: Lipopolysaccharide; DCs: Dendritic cells; HSCs: Hepatic stellate cells; LSECs: Liver sinusoidal endothelial cells; IFNs: Interferons; DC: Dendritic cell; MyD88: Myeloid differentiation primary response protein 88.