Open AccessHuman intrahepatic ILC2 are IL-13positive amphiregulinpositive and their frequency correlates with model of end stage liver disease score
Author(s) -
Hannah C. Jeffery,
Patrick McDowell,
Philipp Lutz,
Rebecca E. Wawman,
Stephen K. Roberts,
Christopher Bagnall,
Jane Birtwistle,
David H. Adams,
Ye Htun Oo
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0188649
Subject(s) - amphiregulin , ccl20 , innate lymphoid cell , hepatic stellate cell , interleukin 7 receptor , biology , inflammation , immunology , chemokine , liver disease , immune system , receptor , pathology , medicine , t cell , il 2 receptor , chemokine receptor , innate immune system , epidermal growth factor receptor
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 (CRTH2 neg CD117 neg ) subset constituting around 70% of intrahepatic ILCs. Both NCR pos (NKp44 + ) and NCR neg ILC3 (CRTH2 neg CD117 pos ) subsets were also detected. ILC2 (CRTH2 pos ) 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.