Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology

The liver is a central immunological organ. Liver resident macrophages, Kupffer cells (KC),but also sinusoidal endothelial cells, dendritic cells (DC) and other immune cells are involved in balancingimmunity and tolerance against pathogens, commensals or food antigens. Hepatic stellate cells (HSCs)have been primarily characterized as the main effector cells in liver fibrosis, due to their capacity totransdifferentiate into collagen-producing myofibroblasts (MFB). More recent studies elucidated thefundamental role of HSC in liver immunology. HSC are not only the major storage site for dietary vitaminA (Vit A) (retinol, retinoic acid), which is essential for proper function of the immune system. This pericytefurther represents a versatile source of many soluble immunological active factors including cytokines [e.g.,interleukin 17 (IL-17)] and chemokines [C-C motif chemokine (ligand) 2 (CCL2)], may act as an antigenpresenting cell (APC), and has autophagy activity. Additionally, it responds to many immunological triggersvia toll-like receptors (TLR) (e.g., TLR4, TLR9) and transduces signals through pathways and mediatorstraditionally found in immune cells, including the Hedgehog (Hh) pathway or inflammasome activation.Overall, HSC promote rather immune-suppressive responses in homeostasis, like induction of regulatoryT cells (Treg), T cell apoptosis (via B7-H1, PDL-1) or inhibition of cytotoxic CD8 T cells. In conditionsof liver injury, HSC are important sensors of altered tissue integrity and initiators of innate immune cellactivation. Vice versa, several immune cell subtypes interact directly or via soluble mediators with HSC. Suchinteractions include the mutual activation of HSC (towards MFB) and macrophages or pro-apoptotic signalsfrom natural killer (NK), natural killer T (NKT) and gamma-delta T cells (γδ T-cells) on activated HSC.Current directions of research investigate the immune-modulating functions of HSC in the environmentof liver tumors, cellular heterogeneity or interactions promoting HSC deactivation during resolution ofliver fibrosis. Understanding the role of HSC as central regulators of liver immunology may lead to noveltherapeutic strategies for chronic liver diseases.