P2X1-regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regeneration
Open accessAbstract
Unlabelled 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. Conclusion This study shows that innate immune cell-derived IL-22 is required for efficient liver regeneration and that s…
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IL-22 is a mediator of cross-talk between immune cells and hepatocytes and contributes to efficient liver regeneration but potentially distinct from IL-6 primarily contributes to long-term recovery.
“Together these studies suggest that IL-22 is a mediator of the cross-talk between immune cells and hepatocytes and contributes to efficient liver regeneration but potentially distinct from IL-6 primarily contributes to long-term recovery.”
From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Kudira et al., 2016
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“Analysis of IL-22 knockout mice revealed that in the absence of IL-22 hepatocellular proliferation at 48 h post hepatectomy is reduced (Kudira et al., 2016).”
Background
- Authors
- Kudira, R., Malinka, T., Kohler, A., Dosch, M., de Agüero, M. G., Melin, N., Haegele, S., Starlinger, P., Maharjan, N., Saxena, S., Keogh, A., Stroka, D., Candinas, D., & Beldi, G.
- Affiliations
- University of Bern (CH)
- Department of Gastroenterology/Mucosal Immunology,Bern University Hospital,University of Bern,Bern,Switzerland
- Department for Visceral Surgery and Medicine,Bern University Hospital,University of Bern,Bern,Switzerland
- Vienna General Hospital (AT)
- Corresponding author
- Beldi, Guido
- ORCID
- Venue
- Hepatology
- Published
- 2016-03-17
- Volume
- 63
- Issue
- 6
- Pages
- 2004-2017
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W2270525566
- Cited by
- 50
- References
- 0
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 7 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 7 · 2016: 5
- FWCI
- 4.33
- Type
- journal article
- Language
- en
- Open access
- green
- boris.unibe.ch
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, other-oa)
- BORIS (University Library Bern) (submittedVersion)
- Open Access CRIS of the University of Bern
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (146986, 310030_146986/1, 130816)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- IL-22, liver regeneration, P2X1 receptor, P2Y6 receptor, ATP, partial hepatectomy, IL-23, hepatocyte proliferation, endoplasmic reticulum stress, liver injury, hepatoprotection
- MeSH terms
- Interleukin-22, Adenosine Triphosphate, Animals, Hepatectomy, Humans, Interleukins, Killer Cells, Natural, Liver Regeneration, Male, Mice, Inbred C57BL, Receptors, Purinergic P2X1, Endoplasmic Reticulum Stress
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