2. Academic Validation
  3. B cell-derived acetylcholine promotes liver regeneration by regulating Kupffer cell and hepatic CD8+ T cell function

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

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: tak.mak@uhn.ca.
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.

Figures
Products