Abstract
Toll-like Receptor 3 (TLR3) is a pathogen pattern recognition receptor that plays a key role in innate immunity. TLR3 signalling has numerous functions in liver, both in health and disease. Here we report that TLR3 is expressed by quiescent hepatic stellate cells (HSC) where it functions to induce transcription and secretion of functional interferons as well as a number of other cytokines and chemokines. Upon transdifferentiation into myofibroblasts, HSCs rapidly loose the ability to produce interferon gamma (IFNγ). Mechanistically, this gene silencing may be due to Polycomb complex mediated repression via methylation of histone H3 lysine 27. In contrast to wild type, quiescent HSC isolated from tlr3 knockout mice do not produce IFNγ in response to Poly(I∶C) treatment. Therefore, quiescent HSC may contribute to induction of the hepatic innate immune system in response to injury or infection.
Highlights
Hepatic stellate cells (HSC) are specialised pericytes of the liver sinusoids found in the Space of Disse, a basement membrane-like structure located between columns of hepatocytes and sinusoidal endothelial cells [1]
We focused on Toll-like Receptor 3 (TLR3), a sensor of dsRNA, which is expressed at relatively high levels on both quiescent HSCs (qHSC) and activated HSC (aHSC) but has distinct functions in these two phenotypic states
Western blot analysis confirmed that TLR3 protein is expressed in both qHSC and aHSC, no significant change in expression occurred with activation (Figure 1B)
Summary
Hepatic stellate cells (HSC) are specialised pericytes of the liver sinusoids found in the Space of Disse, a basement membrane-like structure located between columns of hepatocytes and sinusoidal endothelial cells [1]. The most characterised function of HSCs is the ability to transdifferentiate from a quiescent phenotype into highly proliferative, contractile and wound-healing myofibroblast [2] This so-called activated HSC (aHSC) produces vast quantities of fibril-forming collagens and promotes net deposition of fibrotic extracellular matrix, a process important for repair following infection or trauma to the liver. Several investigators have described that qHSC possess multiple thorn-like cytoplasmic extensions which can protrude into the sinusoidal space or make direct contact with hepatocytes. These membrane projections have been shown to function as a leading edge for the qHSC and play a role in sensing of extracellular factors that influence HSC phenotype. Given the anatomical location of qHSCs and their morphology, they have the potential to operate as sinusoidal sentinels, detecting mechanical or biochemical alterations in hepatocytes, endothelial cells, within the Space of Disseor even within the sinusoidal spaces [4]
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