Liver Sinusoidal Endothelial Cells Contribute to Hepatic Antigen-Presenting Cell Function and Th17 Expansion in Cirrhosis

Abstract

Hepatic immune function is compromised during cirrhosis. This study investigated the immune features of liver sinusoidal endothelial cells (LSECs) in two experimental models of cirrhosis. Dendritic cells, hepatic macrophages, and LSECs were isolated from carbon tetrachloride and bile duct-ligated rats. Gene expression of innate receptors, bacterial internalization, co-stimulatory molecules induction, and CD4+ T cell activation and differentiation were evaluated. Induced bacterial peritonitis and norfloxacin protocols on cirrhotic rats were also carried out. LSECs demonstrated an active immunosurveillance profile, as shown by transcriptional modulation of different scavenger and cell-adhesion genes, and their contribution to bacterial internalization. LSECs significantly increased their expression of CD40 and CD80 and stimulated CD4+ T cell activation marker CD71 in both models. The pro-inflammatory Th17 subset was expanded in CCl4-derived LSECs co-cultures. In the bile duct ligation (BDL) model, CD4+ T cell differentiation only occurred under induced bacterial peritonitis conditions. Differentiated pro-inflammatory Th cells by LSECs in both experimental models were significantly reduced with norfloxacin treatment, whereas Foxp3 tolerogenic Th CD4+ cells were expanded. Conclusion: LSECs’ participation in the innate-adaptive immune progression, their ability to stimulate pro-inflammatory CD4+ T cells expansion during liver damage, and their target role in norfloxacin-induced immunomodulation granted a specific competence to this cell population in cirrhosis.

Gene Signatures Detect Damaged Liver Sinusoidal Endothelial Cells in Chronic Liver Diseases

“…LSEC permeability is important for liver function as it permits plasma, solutes, and small substrates such as albumin ( 3 ) and insulin ( 4 ) to diffuse from the blood toward the parenchymal cells. Besides working as a filter and first barrier of the liver, these cells have other functions such as the production of coagulation factor VIII ( 5 ), antigen presentation ( 6 , 7 ), leukocyte recruitment and endocytosis of virus particles ( 8 ), oxidized LDL ( 9 ) and immunocomplexes by the abundant expression of multiple scavenger receptors ( 10 ). Expression of specific scavenger receptors and other characteristic proteins can vary across the liver acinus ( 11 , 12 ).…”

The evolving role of liver sinusoidal endothelial cells in liver health and disease

“…[70] In chronic liver disease, however, these tolerogenic properties of LSECs may be altered, as shown in an animal model of cirrhosis in which LSECs functioned as Ag-presenting cells to stimulate a proinflammatory CD4 + Th17 T-cell response. [71] Because of their propensity for inducing tolerance, LSECs are an intriguing target for therapeutics for autoimmune disease. One recent study has tested this approach, utilizing LSEC-selective oleic acid-stabilized superparamagnetic iron oxide nanoparticles loaded with an autoantigen in a mouse model of autoimmune cholangitis.…”

“…Additional details of the tolerogenic mechanisms of LSECs have recently been described, revealing that LSECs block metabolic changes that are associated with a more immunogenic Ag-presenting phenotype in response to lipopolysaccharide in other Ag-presenting cells, and that LSEC-primed CD8 T cells develop into a unique population of memory cells through IL-6 transsignaling and Stat3 signaling leading to upregulation of FOXO1 70 . In chronic liver disease, however, these tolerogenic properties of LSECs may be altered, as shown in an animal model of cirrhosis in which LSECs functioned as Ag-presenting cells to stimulate a proinflammatory CD4+ Th17 T-cell response 71 …”

Why is endothelial resilience key to maintain cardiac health?

“…This proatherogenic phenotype was associated with increased expression of typical markers of macrophages, including major histocompatibility complex II (MHCII). Specialized endothelium, like sinusoidal ECs in the liver, has antigen-presenting functions, and can act as sentinel cells, sensing bacterial infections and cross-prime T cells to activation [15,112,121]. In the heart, the presence of MHCII-positive ECs with antigen-presenting activities has been described already in the 1990s [106].…”