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Why Liver Sinusoidal Endothelial Cells Are Essential

The liver’s sinusoidal endothelial cells (or LSEC) are essential to the liver’s health. They are responsible for a wide range of functions, including regulating the inflammatory and immune responses of the liver and forming the pre-metastatic niche, the location where new blood vessels form in the body. Therefore, failure to maintain the integrity of these cells can lead to complications like fibrosis or cancer.

Autophagy

Sinusoidal endothelial cells in the liver play critical roles in metabolism. In addition, they are essential scavenger cells. The defenestration of these cells is associated with the development of liver fibrosis. Therefore, autophagy in these cells has been investigated. However, the mechanisms of autophagy in sinusoidal endothelial cells are still unclear.

The present study focused on determining the effects of impaired liver autophagy on hepatic inflammation. We used the Atg5lox/lox; VE-cadherin-Cre mice model, which exhibited autophagy defects. Significant changes in inflammatory pathways accompanied this condition. Our findings suggest that autophagy in LSECs may play a critical role in liver fibrogenesis.

We compared the gene expression of TSECs deficient in autophagy with control TSECs. These results showed that TSECs deficient in autophagy exhibited increased Ccl5 and VEGF-A levels and strongly correlated with genes involved in angiogenesis. After exposure to TNFa, TSECs deficient in autophagy showed more TGF-b1 levels than control TSECs. Moreover, autophagic degradation of Cav-1 promoted the PI3K-AKT-MTOR pathway in LSECs.

Autophagic flux was also assessed. For this purpose, TSECs were transduced with lentivirus expressing a control shRNA or Atg5lox/lox; VE-cadherin-Cre. TSECs were then exposed to shear stress for 24 h. The number of autophagic vacuoles in LSECs was measured by flow cytometry. Compared to the LSECs in the control condition, the TSECs that were deficient in autophagy showed a decreased rate of autophagic flux.

Regulation of inflammatory and immune responses

The liver sinusoidal endothelial cells are essential for metabolic homeostasis and waste clearance. They also play a critical role in regulating inflammatory and immune responses. However, the mechanisms underlying the activity of these cells in the liver still need to be better understood. This has led to an interest in developing therapeutics targeting these cells.

LSEC are characterized by their endocytic capacity, lysosomal processing of blood-borne proteins, and adhesion to blood vessels and other tissue. During inflammation, they recruit leukocytes and can present chemokine ligands on the cell surface that facilitate leukocytes’ adhesion. These ligands can also help to maintain the firm adhesion of leukocytes and to promote their transmigration in an integrin-dependent manner.

Liver sinusoidal endothelial cells have been shown to exhibit an active immunosurveillance profile. In addition, these cells increase the expression of atypical adhesion molecules, such as CXCL16. This facilitates the recruitment of distinct leukocyte subsets, including the T-cells, dendritic cells (DCS), Kupffer cells, NK cells, and Teff cells.

LSEC plays a central role in regulating the immune microenvironment during chronic inflammation. This includes recruiting a specific hepatic APC population, which regulates the immune response and facilitates liver regeneration. During hepatic infections, these APCs limit inflammation and produce immunosuppressive cytokines.

As part of the immune response, LSEC activates CD4+ T cells. Through a combination of atypical adhesion molecules and scavenger receptors, these cells can initiate T-cell trafficking into the liver and differentiate into immunosuppressive regulatory T-cells. LSEC also promotes the recruitment of apoptosis-inducing NK cells.

Pre-metastatic niche formation

Liver sinusoidal endothelial cells (LSEC) are key players in metabolic homeostasis, fibrosis, and immune tolerance. Unfortunately, they also contribute to secondary tumors, including liver cancer. It is, therefore, essential to understanding their function. In particular, LSEC plays a crucial role in pre-metastatic niche formation.

The formation of a pre-metastatic niche occurs several years before the appearance of a metastatic tumor. It is known that cancer cells can mimic the homing and survival capabilities of liver immune sentinels, promoting colonization and migration of blood-borne cancer cells into the sinusoidal lumen. LSEC contributes to establishing a hospitable hepatic metastatic niche through the secretion of pro-metastatic mediators such as PLVAP, SDF1a, and PDGFb. This provides a promising therapeutic intervention.

LSEC contributes to the trafficking of leukocytes into the liver. However, LSEC also participates in the recruitment of different immunosuppressive leukocyte subsets. These include NK cells, CD4+ T cells, and Treg cells. Leukocyte recruitment is triggered by a series of steps in an adhesion cascade involving receptor-ligand interactions and transmigration.

When a tumor reaches the liver, it initiates an adhesion cascade by releasing soluble mediators. LSEC contributes to the recruitment of different leukocyte subsets through the secretion of atypical adhesion molecules and SCARF1. Among the atypical adhesion molecules, ICAM-1 is implicated in developing liver metastases from colorectal cancer.

Inhibition of LSEC capillarization and dysfunction may promote fibrosis regression.

LSECs play a critical role in liver fibrosis development and regeneration. In addition, LSECs have unique morphological characteristics. They are also highly efficient in clearing viral particles from the blood. This ability has increased attention to LSEC and its role in hepatic disease. However, the molecular and cellular mechanisms underlying the phenotype of LSECs have yet to be understood.

LSECs represent the first liver cell population exposed to toxic stimuli. As such, LSECs are responsible for fine-tuning responses to injury. For example, LSECs control immune zone formation in the liver. These cells also modulate vascular thrombosis and coagulation. Toll-like receptor (TLR)-2 expression by LSECs is critical in modulating vascular thrombosis.

The NF-kB signaling pathway can also control LSECs. Curcumol intervention reduces PNF-kB expression in this pathway. This inhibition may promote fibrosis regression by inhibiting the inflammatory response. The NF-kB pathway regulates the production of VEGF, a crucial endocrine factor. In addition, it acts as a chromatin opener for the KLF2-dependent regulation of anticoagulant thrombomodulin expression.

Notch is also a central regulator of eNOS-sGC signaling. Loss of eNOS-sGC signaling, a hallmark of fibrosis, causes sinusoidal capillarization and impairs LSEC functions. Consequently, LSECs lose their fenestrae. Without a functioning fenestrae, LSECs are unable to function as anti-inflammatory cells.

Several genes associated with sinusoidal capillarization are downregulated during NASH. For example, TF family member Tbx3 is decreased in sinusoidal vasculature compared to other vascular beds. Furthermore, the sinusoidal EC is exposed to a large number of pathogens. These pathogens enter the liver via the portal vein. During liver fibrosis, these pathogens can trigger hepatocyte activation. Activated HSCs produce excess extracellular matrix and fibrosis.

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