Human intrahepatic ILC2 are IL-13*positive Amphiregulin*positive and their frequency correlates with Model of End stage Liver Disease score

Research output: Contribution to journalArticle

Authors

  • Patrick McDowell
  • Philipp Lutz
  • Rebecca E Wawman
  • Sheree Roberts
  • Christopher Bagnall

External organisations

  • Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology & Immunotherapy, University of Birmingham, UK
  • Department of Internal Medicine, University of Bonn, Bonn, Germany
  • School of Life Sciences, Faculty of Health and Life Sciences, Coventry University, Coventry, UK

Abstract

INTRODUCTION: Innate lymphoid cells (ILC) have been implicated in the initiation of inflammation and fibrosis in mice. However, ILC have not been characterized in inflamed human liver tissue.

METHODS: Human intrahepatic lymphocytes were isolated by mechanical digestion and phenotyped by flow cytometry. Conditioned medium from cultures of primary human biliary epithelial cells, stellate cells, fibroblasts and inflamed human liver tissue was used to model the effects of the inflammatory liver environment of ILC phenotype and function.

RESULTS: All three ILC subsets were present in the human liver, with the ILC1 (CRTH2negCD117neg) subset constituting around 70% of intrahepatic ILCs. Both NCRpos (NKp44+) and NCRneg ILC3 (CRTH2negCD117pos) subsets were also detected. ILC2 (CRTH2pos) frequency correlated with disease severity measured by model of end stage liver disease (MELD) scoring leading us to study this subset in more detail. ILC2 displayed a tissue resident CD69+ CD161++ phenotype and expressed chemokine receptor CCR6 allowing them to respond to CCL20 secreted by cholangiocytes and stellate cells. ILC2 expressed integrins VLA-5 and VLA-6 and the IL-2 and IL-7 cytokine receptors CD25 and CD127 although IL-2 and IL-7 were barely detectable in inflamed liver tissue. Although biliary epithelial cells secrete IL-33, intrahepatic ILC2 had low expression of the ST2 receptor. Intrahepatic ILC2 secreted the immunoregulatory and repair cytokines IL-13 and amphiregulin.

CONCLUSIONS: Intrahepatic ILC2 express receptors allowing them to be recruited to bile ducts in inflamed portal tracts. Their frequencies increased with worsening liver function. Their secretion of IL-13 and amphiregulin suggests they may be recruited to promote resolution and repair and thereby they may contribute to ongoing fibrogenesis in liver disease.

Details

Original languageEnglish
Article numbere0188649
JournalPLoS ONE
Volume12
Issue number12
Publication statusPublished - 19 Dec 2017

Keywords

  • Amphiregulin, End Stage Liver Disease, Epithelial Cells, Humans, Immunity, Innate, Inflammation, Integrins, Interleukin-13, Interleukin-2, Interleukin-2 Receptor alpha Subunit, Interleukin-7, Liver, Lymphocyte Count, Lymphocytes, Models, Biological, NK Cell Lectin-Like Receptor Subfamily B, Phenotype, Receptors, Chemokine, Receptors, Immunologic, Receptors, Prostaglandin, Journal Article

ASJC Scopus subject areas