https://pubmed.ncbi.nlm.nih.gov/37078450/ biliary atresia

Hepatology. 2023 Apr 21.
doi: 10.1097/HEP.0000000000000418. Online ahead of print
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Plasticity between ILC2 subsets and amphiregulin expression regulate epithelial repair in biliary atresia

Abigail E Russi 1 2, Pranavkumar Shivakumar 1 2, Zhenhua Luo 3, Jorge Bezerra 4

Abstract

Background aims: While a dysregulated type 1 immune response is integral to the pathogenesis of biliary atresia, studies in both humans and mice have uncovered a type 2 response, primarily driven by type 2 innate lymphoid cells. In non-hepatic tissues, natural ILC2s (nILC2s) regulate epithelial proliferation and tissue repair, whereas inflammatory ILC2s (iILC2s) drive tissue inflammation and injury. The aim of this study is to determine the mechanisms used by ILC2 subpopulations to regulate biliary epithelial response to an injury.

Approach results: Using Spearman correlation analysis, nILC2 transcripts, but not those of iILC2s, are positively associated with cholangiocyte abundance in biliary atresia patients at time of diagnosis. Natural ILC2s are identified in the mouse liver via flow cytometry. They undergo expansion and increase amphiregulin production after IL-33 administration. This drives epithelial proliferation dependent on the IL-13/IL-4Rα/STAT6 pathway as determined by decreased nILC2s and reduced epithelial proliferation in knockout strains. The addition of IL-2 promotes inter-lineage plasticity towards an nILC2 phenotype. In experimental biliary atresia induced by rotavirus, this pathway promotes epithelial repair and tissue regeneration. The genetic loss or molecular inhibition of any part of this circuit switches nILC2s to iILC2-like, resulting in decreased amphiregulin production, decreased epithelial proliferation, and the full phenotype of experimental biliary atresia.

Conclusions: These findings identify a key function of the IL-13/IL-4Rα/STAT6 pathway in ILC2 plasticity and an alternate circuit driven by IL-2 to promote nILC2 stability and amphiregulin expression. This pathway induces epithelial homeostasis and repair in experimental biliary atresia.