title: P2X1-regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regeneration.
abstract: Paracrine signalling mediated by 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 whether IL-22 is critical for the crosstalk between liver lymphocytes and parenchymal cells during liver regeneration after partial hepatectomy (PH). 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 PH, 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-PH are conventional natural killer cells and innate lymphoid cells type 1. Extracellular adenosine triphosphate (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.
  
  
  
  This study shows that innate immune cell-derived IL-22 is required for efficient liver regeneration and that secretion of IL-22 in the regenerating liver is modulated by the ATP receptor, P2X1. (Hepatology 2016;63:2004-2017).
authors: Department for Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Ramesh
authors: R
authors: Kudira
authors: Department for Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Thomas
authors: T
authors: Malinka
authors: Department for Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Andreas
authors: A
authors: Kohler
authors: Department for Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Michel
authors: M
authors: Dosch
authors: Department of Gastroenterology/Mucosal Immunology, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Mercedes Gomez
authors: MG
authors: de Agüero
authors: Department for Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Nicolas
authors: N
authors: Melin
authors: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors: Stefanie
authors: S
authors: Haegele
authors: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors: Patrick
authors: P
authors: Starlinger
authors: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors: Niran
authors: N
authors: Maharjan
authors: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors: Smita
authors: S
authors: Saxena
authors: Department for Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Adrian
authors: A
authors: Keogh
authors: Department for Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Deborah
authors: D
authors: Stroka
authors: Department for Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Daniel
authors: D
authors: Candinas
authors: Department for Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Guido
authors: G
authors: Beldi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D059865:Endoplasmic Reticulum Stress; D006498:Hepatectomy; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism*; D008115:Liver Regeneration; D008297:Male; D008810:Mice, Inbred C57BL; D058474:Receptors, Purinergic P2X1 / Q000378:metabolism*; D000097043:Interleukin-22
chemical_list: D000255:Adenosine Triphosphate; D007378:Interleukins; D058474:Receptors, Purinergic P2X1; D000097043:Interleukin-22