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

Esther Caparrós,Oriol Juanola,Pedro Zapater,Fabián Tarín,Jordi Gracia-Sancho,José M González-Navajas,Rubén Francés,Amaya Puig-Kroger,Raquel Linares,Isabel Gómez-Hurtado,Sebastián Martínez-López,Paula Piñero

doi:10.3390/cells9051227

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.

Highlights

The development and progression of cirrhosis are associated with an immunological dysfunction as one major factor in the increased susceptibility to bacterial infections, a frequent and clinicallyCells 2020, 9, 1227; doi:10.3390/cells9051227 www.mdpi.com/journal/cellsCells 2020, 9, 1227 relevant complication in the evolution of cirrhotic patients [1]
We showed that liver sinusoidal endothelial cells (LSECs) were versatile antigen-presenting cells able to differentiate a CD4+ Th17 adaptive response in the inflammatory context of CCl4 -induced experimental cirrhosis
LSECs modulated their innate receptor’s transcriptional profile, bridged innate and adaptive immunity by inducing the expression of co-stimulatory molecules, cooperated in phagocytic tasks, and activated CD4+ T cells to differentiate effector Th responses in cirrhosis

Summary

Introduction

Cells 2020, 9, 1227 relevant complication in the evolution of cirrhotic patients [1] This (endogenous) bacterial load is delivered into the liver through the portal circulation and, even in the absence of overt infection, the hepatic immune system continuously faces gut-derived antigens that require efficient clearance to avoid disease complications [2]. These events call attention to the cells responsible for hepatic immune surveillance in the context of liver failure. The different receptors are responsible for the clearance of continuously incoming pathogenic antigens and complement intermediaries, and for leukocyte adhesion and infiltration to inflamed tissues when recruited [4]

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