REVIEWS Liver sinusoidal endothelial cells — gatekeepers of hepatic immunity Shishir Shetty1,2, Patricia F. Lalor1,2 and David H. Adams1,2* Abstract | Liver sinusoidal endothelial cells (LSECs) line the low shear, sinusoidal capillary channels of the liver and are the most abundant non- parenchymal hepatic cell population. LSECs do not simply form a barrier within the hepatic sinusoids but have vital physiological and immunological functions, including filtration, endocytosis, antigen presentation and leukocyte recruitment. Reflecting these multifunctional properties, LSECs display unique structural and phenotypic features that differentiate them from the capillary endothelium present within other organs. It is now clear that LSECs have a critical role in maintaining immune homeostasis within the liver and in mediating the immune response during acute and chronic liver injury. In this Review , we outline how LSECs influence the immune microenvironment within the liver and discuss their contribution to immune-mediated liver diseases and the complications of fibrosis and carcinogenesis. Sinusoidal endothelial cells line what constitutes a vitelline veins, whereas sinusoids develop from capillary unique vascular bed in the liver, which receives blood vessels of the septum transversum and acquire their from both the hepatic artery and the portal veins into distinctive fenestrated phenotype by week 20 of gesta- the hepatic parenchyma (Fig. 1). Studies of these cells tion7 under the control of transcription factor GATA4 isolated from animals usually refer to them as liver (REF.8). From this point onward, sinusoidal endothelial sinusoidal endothelial cells (LSECs), whereas isolated cells remain functionally and phenotypically distinct human cells have also been referred to as human hepatic from the other vascular endothelial cells in the liver sinusoidal endothelial cells (HSECs). For the purpose microenvironment and assume a phenotype that has of this Review, we use the term LSEC. The exposure of many similarities with lymphatic endothelial cells9. The these sinusoidal endothelial cells to blood originating unique characteristics of LSECs are presented in BOx 1. from both the gut and the systemic circulation means Both lymphatic and sinusoidal endothelial cells have they are ideally situated to remove and recycle blood- minimal basement membranes and loosely organized borne proteins and lipids. In combination with Kupffer cell junctions10 and share a complement of receptors cells (KCs; liver- resident macrophages), LSECs consti- such as lymphatic vessel endothelial hyaluronic acid tute the most powerful scavenger system in the body1. receptor (LYVE1)11, prospero homeobox protein 1 This activity is facilitated by the presence of fenestrae (PROX1)12, podoplanin13 and liver/lymph node-specific in LSECs, their lack of a classical basement membrane ICAM3-grabbing non- integrin (LSIGN; also known as and their expression of promiscuous scavenger receptors CLEC4M)14. It has been shown that the phenotype of combined with the most potent endocytic capacity in sinusoidal endothelial cells varies across the liver acinus; the body2. Thus, virus particles3, advanced glycation end a study of human liver tissue published in 2017 demon- 4 5 hi low 1 products and modified LDL cholesterol can be cleared strated that zone 1 LSECs are CD36 and LYVE1 , Centre for Liver Research low hi and NIHR Birmingham from the circulation within minutes by this route. whereas zone 2 and zone 3 LSECs are CD36 , LYVE1 hi 15 Biomedical Research Centre, Endothelial cells in different vascular beds are gener- and CD32 (REF. ). The presence of fenestrations or Institute of Immunology and ated from common early embryological precursors and membranous pores organized into sieve plates is a fea- Immunotherapy, University of have broadly similar histological appearance and func- ture that also distinguishes LSECs from the other hepatic Birmingham, Birmingham, UK. tional roles throughout the body. However, extensive endothelial populations2. 2 Liver Unit, University variations in phenotype and function arise as a conse- Fenestrations are not unique to hepatic endothelial Hospitals Birmingham NHS Trust, Birmingham, UK quence of local microenvironmental signals dependent cells and are also found in endothelium in endocrine 6 16 17 18 *e- mail: d.h.adams@ on anatomical localization . The vascular architecture glands such as the pancreas , kidney , spleen and bone 19 bham.ac.uk in the human liver is acquired by 17–25 weeks of gesta- marrow and are sometimes observed in tumour vas- 20 https://doi.org/10.1038/ tion, but different vessels within the liver have distinct culature . However, unlike other fenestrated endothe- s41575-018-0020-y embryonic origins. Thus, portal vessels are derived from lial populations such as those in the kidney, hepatic NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 15 | SEPTEMBER 2018 | 555 REVIEWS Key points LSECs. Chronic exposure of both KCs and LSECs to LPS leads to an LPS- refractory state, and in LSECs specifi- • Liver sinusoidal endothelial cells (LSECs) that line the hepatic sinusoids have cally, LPS exposure is associated with reduced nuclear important physiological roles and mediate the filtration and scavenger functions translocation of nuclear factor- κB (NF- κB) and subse- of the liver. quent reduced leukocyte adhesion32. This mechanism • LSECs also have innate and adaptive immunological functions, including antigen prevents the liver from being in a constantly activated presentation and maintenance of the balance between tolerance and effector inflamed state in response to the constant exposure to immune responses. bacterial products from the gut. Studies of other TLRs • In inflammatory liver diseases, LSECs influence the composition of hepatic immune demonstrate that LSECs can respond to signals medi- populations by mediating diapedesis of leukocyte subsets via distinct combinations of adhesion molecules and chemokines. ated via TLR1–TLR4, TLR6, TLR8 and TLR9, but their activation has cell-specific responses that are restricted • LSECs play a crucial part in the cellular crosstalk that regulates progressive chronic liver disease, which leads to fibrosis and carcinogenesis. compared with classical antigen-presenting cells, thereby contributing to an organ- specific response to antigens • The role of LSECs in initiating immune responses and contributing to progressive 33 liver disease makes them a potential therapeutic target for treating inflammatory and the tolerogenic environment of the liver . liver diseases. A unique characteristic of LSECs is their expression of high levels of several scavenger receptors compared with conventional endothelium. Scavenger receptors are fenestrations lack a diaphragm or basal lamina and are a diverse family of pattern recognition receptors that, grouped into organized sieve plates, rendering LSECs like TLRs, are highly evolutionarily conserved34. In highly permeable (Fig. 1d). Many studies have impli- contrast to TLRs, they were believed to be function- cated vascular endothelial growth factor (VEGF) as ally redundant and to perform silent uptake of ligands. an essential factor for regulation of fenestrations21, However, gathering evidence suggests that this is not but dynamic changes in hepatic fenestration number the case and that scavenger receptors have an impor- and size can occur rapidly in response to agents such tant cell- specific role in immune responses34. They have as alcohol22, diet ary constituents23 and fasting24 or cal- been shown to promote potent pro- inflammatory and orie restriction25. The fenestrations act as a ‘dynamic anti- inflammatory signalling as well as to directly inter- filter’ (REF.26) to permit the access of macromolecules to act with TLRs. Membrane- bound scavenger receptors parenchymal cells, and in addition, these pores might recognize their extracellular ligands, which leads to allow circulating viruses to gain access to hepatocytes27. internalization of the ligand, termed endocytosis, and Evidence from animal studies suggests that fenestrations trafficking from the cell membrane to intracellular com- can constitute up to 40% of the cell and that the size, dis- partments such as endosomes. The high levels of scav- tribution and clustering of the pores in sieve plates varies enger receptors on LSECs give them a high endocytic with the zonal distribution of the endothelium28 and across capacity. One of the most extensively studied scavenger the endothelial surface. Up to one- third of these pores receptors on LSECs is the mannose receptor (MR)1,35,36. are organized into complex labyrinths, and many are Others include the homologous scavenger receptors sta- associated with components of microtubules29, caveoli bilin 1 and stabilin 2 (REF.37) and related molecules such and coated pits to form a transport network that could as C- type lectins, including the type 2 receptor subclass impose additional regulation on the traffic of material dendritic cell- specific ICAM3-grabbing non- integrin into the cells30, enabling them to govern the movement (DCSIGN; also known as CD209) and LSIGN14,38. of materials to and from the liver parenchyma. The members of the C- type lectin group are involved in varied functions ranging from cell–cell interaction Balancing tolerance and immune response to uptake of serum glycoproteins. A third lectin with The permissive nature of sinusoidal endothelium a similar structure to DCSIGN and LSIGN has been probably evolved to handle the constant