In hepatic fibrosis, liver sinusoidal endothelial cells acquire enhanced immunogenicity

Michael K. Connolly, Andrea S. Bedrosian, Ashim Malhotra, Justin R. Henning, Junaid Ibrahim, Valery Vera, Napoleon E. Cieza-Rubio, Burhan U. Hassan, H. Leon Pachter, Steven Cohen, Alan B. Frey, George Miller

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2200-2208
Number of pages9
JournalJournal of Immunology
Volume185
Issue number4
DOIs
StatePublished - Aug 15 2010

    Fingerprint

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Connolly, M. K., Bedrosian, A. S., Malhotra, A., Henning, J. R., Ibrahim, J., Vera, V., Cieza-Rubio, N. E., Hassan, B. U., Pachter, H. L., Cohen, S., Frey, A. B., & Miller, G. (2010). In hepatic fibrosis, liver sinusoidal endothelial cells acquire enhanced immunogenicity. Journal of Immunology, 185(4), 2200-2208. https://doi.org/10.4049/jimmunol.1000332