P2X1 regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regeneration.

Kudira, Ramesh; Malinka, Thomas; Kohler, Andreas; Dosch, Michel; Gomez de Agüero Tamargo, Maria de la Mercedes; Melin, Nicolas; Haegele, S; Starlinger, P; Maharjan, Niran; Saxena, Smita; Keogh, Adrian; Keogh-Stroka, Deborah M.; Candinas, Daniel; Beldi, Guido (2016). P2X1 regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regeneration. Hepatology, 63(6), pp. 2004-2017. Wiley Interscience 10.1002/hep.28492

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Paracrine signalling mediated via cytokine secretion is essential for liver regeneration after hepatic resection, yet the mechanisms of cellular crosstalk between immune and parenchymal cells are still elusive. Interleukin-22 (IL-22) is released by immune cells and mediates strong hepatoprotective functions. However, it remains unclear if IL-22 is critical for the crosstalk between liver lymphocytes and parenchymal cells during liver regeneration after partial hepatectomy. Here we found that plasma levels of IL-22 and its upstream cytokine IL-23 are highly elevated in patients after major liver resection. In a mouse model of partial hepatectomy, deletion of IL-22 was associated with significantly delayed hepatocellular proliferation and an increase of hepatocellular injury and endoplasmic reticulum stress. Using Rag1-/- and Rag2-/- γc-/- mice we show that the main producers of IL-22 post partial hepatectomy are conventional natural killer cells and innate lymphoid cells type 1. Extracellular ATP, a potent danger molecule, is elevated in patients immediately after major liver resection. Antagonism of the P2 type nucleotide receptors P2X1 and P2Y6 significantly decreased IL-22 secretion ex vivo. In vivo, specific inhibition of P2X1 was associated with decreased IL-22 secretion, elevated liver injury and impaired liver regeneration.

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