B cell-derived acetylcholine promotes liver regeneration by regulating Kupffer cell and hepatic CD8+ T cell function

  • Immunity. 2025 May 13;58(5):1201-1216.e7. doi: 10.1016/j.immuni.2025.04.002.
Nastaran Fazel Modares  1 ,  Liam D Hendrikse  1 ,  Logan K Smith  1 ,  Michael St Paul  1 ,  Jillian Haight  1 ,  Ping Luo  1 ,  Shaofeng Liu  1 ,  Jerome Fortin  2 ,  Frances K Tong  1 ,  Andrew C Wakeham  1 ,  Soode Moghadas Jafari  1 ,  Chunxing Zheng  3 ,  Mackenzie Buckland  1 ,  Robert Flick  4 ,  Jennifer Silvester  1 ,  Thorsten Berger  1 ,  Troy Ketela  1 ,  Simone Helke  1 ,  Erica Foffi  1 ,  Raheleh Niavarani  1 ,  Ryan Mcwilliam  1 ,  Mary E Saunders  1 ,  Isabelle Colonna  1 ,  Bruna Araujo David  5 ,  Tashi Rastogi  5 ,  Woo-Yong Lee  6 ,  Paul Kubes  7 ,  Tak W Mak  8
Affiliations
  • 1. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 2. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
  • 3. Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China.
  • 4. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • 5. Calvin Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Physiology and Pharmacology Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 6. Department of Biomedical and Molecular Science, Queen's University, Kingston, ON K7L 3N6, Canada.
  • 7. Calvin Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Physiology and Pharmacology Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biomedical and Molecular Science, Queen's University, Kingston, ON K7L 3N6, Canada.
  • 8. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China; Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China; Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada. Electronic address: [email protected].
PMID: 40286791 DOI: 10.1016/j.immuni.2025.04.002
Abstract

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+ B cells subjected to partial hepatectomy (PHX) displayed greater mortality due to failed LR. Kupffer cells and hepatic CD8+ 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+ T cells to curtail harmful interferon-gamma (IFNγ) production. Our work offers insights into LR mechanisms that may point to therapies for liver damage.

Keywords
B cells; CD8 T cells; ChAT B cells; IL-6; Kupffer cells; acetylcholine; hepatic repair; liver regeneration; partial hepatectomy; α7 nAChR; α7 nicotinic acetylcholine receptor.
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