B cell-derived acetylcholine promotes liver regeneration by regulating Kupffer cell and hepatic CD8+ T cell function
Liver regeneration (LR) is essential for recovery from acute trauma, cancer surgery, or transplantation. Neurotransmitters such as acetylcholine (ACh) play a role in LR by stimulating immune cells and augmenting hepatocyte proliferation, but the source of this ACh remains unclear. Here, we demonstrated that B cells expressing choline acetyltransferase (ChAT), which synthesizes ACh, were required for LR. Mice lacking ChAT<sup>+</sup> B cells subjected to partial hepatectomy (PHX) displayed greater mortality due to failed LR. Kupffer cells and hepatic CD8<sup>+</sup> T cells expressed the α7 nicotinic ACh receptor (nAChR), and LR was disrupted in mice lacking α7 nAChR. Mechanistically, B cell-derived ACh signaled through α7 nAChR to positively regulate the function of regenerative Kupffer cells and to control the activation of hepatic CD8<sup>+</sup> T cells to curtail harmful interferon-gamma (IFNγ) production. Our work offers insights into LR mechanisms that may point to therapies for liver damage.
Authors
- Tak W. Mak (ORCID: https://orcid.org/0000-0001-6766-861X)
- Jennifer Silvester (ORCID: https://orcid.org/0000-0001-6087-4066)
- Jillian Haight (ORCID: https://orcid.org/0000-0001-7713-6705)
- Andrew Wakeham
- Troy Ketela (ORCID: https://orcid.org/0000-0003-4732-6553)
- Mary Saunders
- Bruna Araújo David (ORCID: https://orcid.org/0000-0001-8486-329X)
- Rohan McWilliam
- Simone Helke
- Frances Tong
- Ping Luo
- Nastaran Fazel Modares
- Michael E. Buckland (ORCID: https://orcid.org/0000-0003-4755-6471)
- Erica Foffi (ORCID: https://orcid.org/0000-0002-6703-4884)
- Thorsten Berger (ORCID: https://orcid.org/0000-0002-3870-5167)
- Paul Kubes (ORCID: https://orcid.org/0000-0002-2835-4244)
- Logan K. Smith
- Michael St. Paul (ORCID: https://orcid.org/0000-0002-5213-6415)
- Robert Flick (ORCID: https://orcid.org/0000-0001-5463-9107)
- Jérôme Fortin
- Soode Moghadas Jafari
- Woo‐Yong Lee (ORCID: https://orcid.org/0000-0002-4702-8540)
- Chunxing Zheng (ORCID: https://orcid.org/0000-0002-8668-0873)
- Shaofeng Liu (ORCID: https://orcid.org/0000-0002-1230-0946)
- Liam D. Hendrikse
- Tashi Rastogi
- Raheleh Niavarani
- Isabelle Colonna
Institutions
- University Health Network (CA)
- University of Toronto (CA)
- Queen's University (CA)
- Hong Kong Science and Technology Parks Corporation (HK)
- Princess Margaret Cancer Centre (CA)
- McGill University (CA)
Publication Details
- Journal
- Immunity
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1016/j.immuni.2025.04.002
- Citations
- 18
- Primary Topic
- Vagus Nerve Stimulation Research
- Type
- article
- Field-Weighted Citation Impact
- 15.16
Funders
- Cancer Research Institute
- Innovation and Technology Commission
- Canadian Institutes of Health Research