In hepatic fibrosis, liver sinusoidal endothelial cells acquire enhanced immunogenicity.
The normal liver is characterized by immunologic tolerance. Primary mediators of hepatic immune tolerance are liver sinusoidal endothelial cells (LSECs). LSECs block adaptive immunogenic responses to Ag and induce the generation of T regulatory cells. Hepatic fibrosis is characterized by both intense intrahepatic inflammation and altered hepatic immunity. We postulated that, in liver fibrosis, a reversal of LSEC function from tolerogenic to proinflammatory and immunogenic may contribute to both the heightened inflammatory milieu and altered intrahepatic immunity. We found that, after fibrotic liver injury from hepatotoxins, LSECs become highly proinflammatory and secrete an array of cytokines and chemokines. In addition, LSECs gain enhanced capacity to capture Ag and induce T cell proliferation. Similarly, unlike LSECs in normal livers, in fibrosis, LSECs do not veto dendritic cell priming of T cells. Furthermore, whereas in normal livers, LSECs are active in the generation of T regulatory cells, in hepatic fibrosis LSECs induce an immunogenic T cell phenotype capable of enhancing endogenous CTLs and generating potent de novo CTL responses. Moreover, depletion of LSECs from fibrotic liver cultures mitigates the proinflammatory milieu characteristic of hepatic fibrosis. Our findings offer a critical understanding of the role of LSECs in modulating intrahepatic immunity and inflammation in fibro-inflammatory liver disease.
Connolly
Michael K
MK
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016, USA.
Bedrosian
Andrea S
AS
Malhotra
Ashim
A
Henning
Justin R
JR
Ibrahim
Junaid
J
Vera
Valery
V
Cieza-Rubio
Napoleon E
NE
Hassan
Burhan U
BU
Pachter
H Leon
HL
Cohen
Steven
S
Frey
Alan B
AB
Miller
George
G
D000818:Animals; D000941:Antigens / Q000276:immunology*; D002251:Carbon Tetrachloride; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013853:Thioacetamide
D000941:Antigens; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D013853:Thioacetamide; D002251:Carbon Tetrachloride