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Identification and characterisation of a hepatic IL-13 producing ILC3-like population potentially involved in liver fibrosis.

Hepatology (Baltimore, Md.)

Authors: Jan Raabe, Kim M Kaiser, Michael ToVinh, Claudia Finnemann, Philipp Lutz, Christoph Hoffmeister, Jenny Bischoff, Felix Goeser, Dominik J Kaczmarek, Tim R Glowka, Steffen Manekeller, Arthur Charpentier, Bettina Langhans, Hans Dieter Nischalke, Marieta Toma, Christian P Strassburg, Ulrich Spengler, Ali T Abdallah, Benjamin Krämer, Jacob Nattermann

OBJECTIVE: Human innate lymphoid cells (ILCs) are critically involved in the modulation of homeostatic and inflammatory processes in various tissues. However, only little is known about the composition of the intrahepatic ILC pool and its potential role in chronic liver disease. Here, we performed a detailed characterisation of intrahepatic ILCs both in healthy and fibrotic livers.

DESIGN: A total of 50 livers (non-fibrotic N = 22; fibrotic N = 29) were analyzed and compared to colon and tonsil tissue (each N = 14) and peripheral blood (N = 32). Human intrahepatic ILCs were characterized ex vivo and upon stimulation using flow cytometry and scRNA-seq. ILC differentiation and plasticity were analyzed by both bulk and clonal expansion experiments. Finally, the effects of ILC-derived cytokines on primary human hepatic stellate cells (HSteCs) were studied.

RESULTS: Unexpectedly, we found that an "unconventional" ILC3-like cell represented the major IL-13-producing liver ILC subset. IL-13 + ILC3-like cells were specifically enriched in the human liver and increased frequencies of this cell type were found in fibrotic livers. ILC3-derived IL-13-production induced upregulation of pro-inflammatory genes in HSteCs, indicating a potential role in the regulation of hepatic fibrogenesis. Finally, we identified KLRG1-expressing ILC precursors as the potential progenitor of hepatic IL-13 + ILC3-like cells.

CONCLUSION: We identified a formerly undescribed subset of IL-13-producing ILC3-like cells that is enriched in the human liver and may be involved in the modulation of chronic liver disease.

Copyright © 2023 American Association for the Study of Liver Diseases.

PMID: 37029085

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