Antigen-specific tolerance and control of autoimmunity effected by liver sinusoidal endothelial cells is unimpaired in liver fibrosis

Frontiers in Immunology

Authors: Cornelia Gottwick, Pia Averhoff, Christian Casar, Laura Anne Liebig, Sabrina Melanie Pilz, Victor Haas, Daria Krzikalla, Sabine Fleischer, Norbert Hübner, Lorenz Adlung, Dorothee Schwinge,  Christoph Schramm, Antonella Carambia, Johannes Herkel

Summary

Liver sinusoidal endothelial cells (LSECs) have a key role in maintaining organismal homeostasis by scavenging blood-borne molecules and inducing specific immune tolerance to ingested antigens. The scavenger and tolerance function of LSECs can be harnessed for specific treatment of autoimmune diseases by nanoparticle-mediated autoantigen delivery to LSECs. In liver fibrosis, which is a frequent condition in human populations, LSECs undergo changes promoting pro-fibrotic and pro-inflammatory activation of other hepatic cells, but it is unclear whether the scavenger and immune tolerance functions of LSECs are affected. Utilizing two mouse models of liver fibrosis, we explored the ability of LSECs to take up nanoparticles conjugated with antigen peptides, to present the ingested antigen peptides to T cells and to induce peptide-specific immune tolerance in vitro and in vivo in the context of autoimmune diseases. LSECs from fibrotic livers showed few distinct adaptations regarding immune functions; however, overall LSEC identity was largely maintained. Accordingly, endocytosis of nanoparticles by LSECs in vivo, as well as processing and presentation of nanoparticle-bound antigen peptides was not compromised by liver fibrosis. LSECs from fibrotic livers maintained the ability to effectively induce the generation of regulatory T cells from conventional CD4 T cells. Hence, targeted delivery of autoantigen peptides to LSECs in vivo effectively induced specific tolerance despite liver fibrosis, providing protection in two models of experimental autoimmune disease. Analysis of datasets from human subjects with or without liver cirrhosis confirmed that scavenger and tolerance pathways in LSECs were preserved in human liver fibrosis. Scavenger activity and antigen-specific tolerance induction by LSECs are preserved in liver fibrosis. Thus, LSECs remain reliable mediators of homeostasis and tolerance under fibrotic conditions, and particularly suitable targets for nanomedicine products.